Human Brainstem Research Articles

Functional modeling of the human auditory brainstem response to broadband stimulation.

Population responses such as the auditory brainstem response (ABR) are commonly used for hearing screening, but the relationship between single-unit physiology and scalp-recorded population responses are not well understood. Computational models that integrate physiologically realistic models of single-unit auditory-nerve (AN), cochlear nucleus (CN) and inferior colliculus (IC) cells with models of broadband peripheral excitation can be used to simulate ABRs and thereby link detailed knowledge of animal physiology to human applications. Existing functional ABR models fail to capture the empirically observed 1.2-2 ms ABR wave-V latency-vs-intensity decrease that is thought to arise from level-dependent changes in cochlear excitation and firing synchrony across different tonotopic sections. This paper proposes an approach where level-dependent cochlear excitation patterns, which reflect human cochlear filter tuning parameters, drive AN fibers to yield realistic level-dependent properties of the ABR wave-V. The number of free model parameters is minimal, producing a model in which various sources of hearing-impairment can easily be simulated on an individualized and frequency-dependent basis. The model fits latency-vs-intensity functions observed in human ABRs and otoacoustic emissions while maintaining rate-level and threshold characteristics of single-unit AN fibers. The simulations help to reveal which tonotopic regions dominate ABR waveform peaks at different stimulus intensities.

Toward an In Vivo Neuroimaging Template of Human Brainstem Nuclei of the Ascending Arousal, Autonomic, and Motor Systems.

Brainstem nuclei (Bn) in humans play a crucial role in vital functions, such as arousal, autonomic homeostasis, sensory and motor relay, nociception, sleep, and cranial nerve function, and they have been implicated in a vast array of brain pathologies. However, an in vivo delineation of most human Bn has been elusive because of limited sensitivity and contrast for detecting these small regions using standard neuroimaging methods. To precisely identify several human Bn in vivo, we employed a 7 Tesla scanner equipped with multi-channel receive-coil array, which provided high magnetic resonance imaging sensitivity, and a multi-contrast (diffusion fractional anisotropy and T2-weighted) echo-planar-imaging approach, which provided complementary contrasts for Bn anatomy with matched geometric distortions and resolution. Through a combined examination of 1.3 mm(3) multi-contrast anatomical images acquired in healthy human adults, we semi-automatically generated in vivo probabilistic Bn labels of the ascending arousal (median and dorsal raphe), autonomic (raphe magnus, periaqueductal gray), and motor (inferior olivary nuclei, two subregions of the substantia nigra compatible with pars compacta and pars reticulata, two subregions of the red nucleus, and, in the diencephalon, two subregions of the subthalamic nucleus) systems. These labels constitute a first step toward the development of an in vivo neuroimaging template of Bn in standard space to facilitate future clinical and research investigations of human brainstem function and pathology. Proof-of-concept clinical use of this template is demonstrated in a minimally conscious patient with traumatic brainstem hemorrhages precisely localized to the raphe Bn involved in arousal.

Abnormal neuronal morphology and neurochemistry in the auditory brainstem of Fmr1 knockout rats

Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder affecting nearly one in 5000 newborn males and is a leading genetic cause of autism spectrum disorder. In addition to developmental delays and intellectual impairment, FXS is characterized by seizures, attention deficit, and hypersensitivity to visual, tactile and auditory stimuli. The Fmr1 gene encodes Fragile X mental retardation protein (FMRP), which is abundant in neurons, binds select mRNAs and functions as a negative regulator of mRNA translation. A deficiency in FMRP, as in FXS and Fmr1 knockout (KO) animals, results in neuronal dysmorphology and altered synaptic function. Additionally, there is evidence for disruption of GABAergic circuits in subjects lacking FMRP. Our previous studies demonstrated widespread expression of FMRP in human auditory brainstem neurons. Given this observation, we hypothesized that FMRP is highly expressed in rat auditory brainstem neurons and that the auditory hypersensitivity characteristic of FXS results from dysfunction of brainstem networks secondary to decreased expression of FMRP. In our investigation of postnatal day 50 (P50) control rats, we found that FMRP was widely expressed in neurons of the superior olivary complex (SOC). In P50 Fmr1 KO rats, many SOC neurons had a smaller soma when compared to controls, indicative of abnormal neuronal morphology. Additionally, neurons in the medial superior olive (MSO) were more round in Fmr1 KO rats. There was also reduced expression of glutamic acid decarboxylase (GAD67) in neurons of the superior paraolivary nucleus (SPON) and a reduction in the number of calretinin-immunoreactive terminals associated with neurons of the medial nucleus of the trapezoid body (MNTB). Together, these findings support the conclusion that the auditory dysfunction characteristic of FXS arises, at least in part, from defective brainstem networks.

Effect of Pulse Rate and Polarity on the Sensitivity of Auditory Brainstem and Cochlear Implant Users to Electrical Stimulation.

To further understand the response of the human brainstem to electrical stimulation, a series of experiments compared the effect of pulse rate and polarity on detection thresholds between auditory brainstem implant (ABI) and cochlear implant (CI) patients. Experiment 1 showed that for 400-ms pulse trains, ABI users’ thresholds dropped by about 2 dB as pulse rate was increased from 71 to 500 pps, but only by an average of 0.6 dB as rate was increased further to 3500 pps. This latter decrease was much smaller than the 7.7-dB observed for CI users. A similar result was obtained for pulse trains with a 40-ms duration. Furthermore, experiment 2 showed that the threshold difference between 500- and 3500-pps pulse trains remained much smaller for ABI than for CI users, even for durations as short as 2 ms, indicating the effect of a fast-acting mechanism. Experiment 3 showed that ABI users’ thresholds were lower for alternating-polarity than for fixed-polarity pulse trains, and that this difference was greater at 3500 pps than at 500 pps, consistent with the effect of pulse rate on ABI users’ thresholds being influenced by charge interactions between successive biphasic pulses. Experiment 4 compared thresholds and loudness between trains of asymmetric pulses of opposite polarity, in monopolar mode, and showed that in both cases less current was needed when the anodic, rather than the cathodic, current was concentrated into a short time interval. This finding is similar to that previously observed for CI users and is consistent with ABI users being more sensitive to anodic than cathodic current. We argue that our results constrain potential explanations for the differences in the perception of electrical stimulation by CI and ABI users, and have potential implications for future ABI stimulation strategies.

P102. Centres of optokinetic adaption control and their functional connectivity in brainstem–cerebellar networks

Several works have revealed a robust visual–vestibular interaction at the cortical level in humans. The same has been shown at an infratentorial level in other primates. Most stimuli applied in the context of ocular motor neuroimaging research are fixed and therefore highly artificial in nature for methodological reasons. Advances in imaging techniques now allow for robust brainstem fMRI, thus opening up a whole new terrain for investigation. The aim of this study was to investigate the neural correlate for ocular motor adaption control (AC) with changing stimulus parameters (speed/direction) and the functional connectivity (FC) of the localised governing hubs at the level of the brainstem and the cerebellum. The effects of constant and linear accelerating small-field optokinetic (OKN) stimuli in the horizontal and vertical direction were studied in 20 volunteers lying supine with their ears plugged in a clinical 3T scanner (Siemens Magnetom Trio, Erlangen, Germany). The protocol included two sessions, each consisting of a T2*-weighted EPI sequence (2mm isotropic resolution, TA 2.93s) in alternating blocks of visual fixation and during OKN stimulation (left/right, up/down). Horizontal (vertical) OKN speeds were either fixed at 30°/s (20°/s) or accelerated during stimulus blocks from 15° to 45°/s (10°/s–30°/s). Resting-state data was acquired prior to task fMRI for 5min (3mm isotropic resolution, 37 slices, TA 2.67s, whole-brain coverage). Data was analysed with SPM8 and DPARSFA after standard preprocessing. T-contrasts were calculated with respect to the rest condition and were considered significant at p . The task revealed a cerebellar network including the dorsal ocular motor vermis (OMV), the fastigial ocular motor region, the posterior inferior vermis, the flocculus and paraflocculus, the culmen (lobule VI) and the declive. In the brainstem, we were able to significantly activate the ocular motor and abducens nuclei, the paramedian pontine reticular formation (PPRF), the dorsolateral pontine nucleus (DLPN), the nucleus reticularis tegmenti pontis (NRTP), the prepositus nucleus (NPH), riMLF and the interstitial nucleus of Cajal (INC). AC was localised to the OMV and pontine structures (NTRB and PPRF). Activation clusters throughout all OKN tasks were significantly larger with higher peak maxima in the left cerebellar hemisphere. We found a significant deactivation of the ventral uvula and the cerebellar tonsils (lobule VIII) during constant more so than during accelerating OKN stimulation. FC maps with the dorsal ocular motor vermis as a seed region gave a significant connectivity with all other regions found in the task-based part of our experiment as well as the dorsal visual stream and all cortical eyefields. Our study gives in vivo evidence for the basic visual–vestibular interactions at the level of the infratentorial networks. Ocular motor areas of the human brainstem could be mapped at an unprecedented detail. AC for the OKN task itself independent of direction was found to be localised mainly in the OMV. Velocity-fixed more so than accelerating OKN stimuli lead to a significant deactivation of a cerebellar core vestibular area known to govern the velocity storage mechanism, the ventral uvula. Extending the cortical concept of a right-hemispheric predominance for visual-spatial processing we found a complementary left-sided dominance for OKN responses in the cerebellum (Dieterich et al., 2003). Taken together, these findings should open up another chapter in our understanding of visual–vestibular interactions in the human brain.

Rapid Increase in Neural Conduction Time in the Adult Human Auditory Brainstem Following Sudden Unilateral Deafness.

Individuals with sudden unilateral deafness offer a unique opportunity to study plasticity of the binaural auditory system in adult humans. Stimulation of the intact ear results in increased activity in the auditory cortex. However, there are no reports of changes at sub-cortical levels in humans. Therefore, the aim of the present study was to investigate changes in sub-cortical activity immediately before and after the onset of surgically induced unilateral deafness in adult humans. Click-evoked auditory brainstem responses (ABRs) to stimulation of the healthy ear were recorded from ten adults during the course of translabyrinthine surgery for the removal of a unilateral acoustic neuroma. This surgical technique always results in abrupt deafferentation of the affected ear. The results revealed a rapid (within minutes) reduction in latency of wave V (mean pre = 6.55ms; mean post = 6.15ms; p < 0.001). A latency reduction was also observed for wave III (mean pre = 4.40ms; mean post = 4.13ms; p < 0.001). These reductions in response latency are consistent with functional changes including disinhibition or/and more rapid intra-cellular signalling affecting binaurally sensitive neurons in the central auditory system. The results are highly relevant for improved understanding of putative physiological mechanisms underlying perceptual disorders such as tinnitus and hyperacusis.

Postmortem diffusion MRI of the human brainstem and thalamus for deep brain stimulator electrode localization.

Deep brain stimulation (DBS) is an established surgical therapy for medically refractory tremor disorders including essential tremor (ET) and is currently under investigation for use in a variety of other neurologic and psychiatric disorders. There is growing evidence that the anti-tremor effects of DBS for ET are directly related to modulation of the dentatorubrothalamic tract (DRT), a white matter pathway that connects the cerebellum, red nucleus, and ventral intermediate nucleus of the thalamus. Emerging white matter targets for DBS, like the DRT, will require improved three-dimensional (3D) reference maps of deep brain anatomy and structural connectivity for accurate electrode targeting. High-resolution diffusion MRI of postmortem brain specimens can provide detailed volumetric images of important deep brain nuclei and 3D reconstructions of white matter pathways with probabilistic tractography techniques. We present a high spatial and angular resolution diffusion MRI template of the postmortem human brainstem and thalamus with 3D reconstructions of the nuclei and white matter tracts involved in ET circuitry. We demonstrate registration of these data to in vivo, clinical images from patients receiving DBS therapy, and correlate electrode proximity to tractography of the DRT with improvement of ET symptoms.

Binaural interaction in human auditory brainstem response compared for tone-pips and rectangular clicks under conditions of auditory and visual attention

Binaural interaction in the auditory brainstem response (ABR) represents the discrepancy between the binaural waveform and the sum of monaural ones. A typical ABR binaural interaction in humans is a reduction of the binaural amplitude compared to the monaural sum at the wave-V latency, i.e., the DN1 component. It has been considered that the DN1 is mainly elicited by high frequency components of stimuli whereas some studies have shown the contribution of low-to-middle frequency components to the DN1. To examine this issue, the present study compared the ABR binaural interaction elicited by tone pips (1 kHz, 10-ms duration) with the one by clicks (a rectangular wave, 0.1-ms duration) presented at 80 dB peak equivalent SPL and a fixed stimulus onset interval (180ms). The DN1 due to tone pips was vulnerable compared to the click-evoked DN1. The pip-evoked DN1 was significantly detected under auditory attention whereas it failed to reach significance under visual attention. The click-evoked DN1 was robustly present for the two attention conditions. The current results might confirm the high frequency sound contribution to the DN1 elicitation.

Functional subdivision of the human periaqueductal grey in respiratory control using 7 tesla fMRI

The periaqueductal grey (PAG) is a nucleus within the midbrain, and evidence from animal models has identified its role in many homeostatic systems including respiration. Animal models have also demonstrated a columnar structure that subdivides the PAG into four columns on each side, and these subdivisions have different functions with regard to respiration. In this study we used ultra-high field functional MRI (7T) to image the brainstem and superior cortical areas at high resolution (1mm3voxels), aiming to identify activation within the columns of the PAG associated with respiratory control. Our results showed deactivation in the lateral and dorsomedial columns of the PAG corresponding with short (~10s) breath holds, along with cortical activations consistent with previous respiratory imaging studies. These results demonstrate the involvement of the lateral and dorsomedial PAG in the network of conscious respiratory control for the first time in humans. This study also reveals the opportunities of 7T functional MRI for non-invasively investigating human brainstem nuclei at high-resolutions.

Multichannel recordings of the human brainstem frequency-following response: Scalp topography, source generators, and distinctions from the transient ABR

Brainstem frequency-following responses (FFRs) probe the neural transcription of speech/music, auditory disorders, and plasticity in subcortical auditory function. Despite clinical and empirical interest, the response's neural basis remains poorly understood. The current study aimed to more fully characterize functional properties of the human FFR (topography, source locations, generation). Speech-evoked FFRs were recorded using a high-density (64 channel) electrode montage. Source dipole modeling and 3-channel Lissajous analysis was used to localize the most likely FFR generators and their orientation trajectories. Additionally, transient auditory brainstem responses (ABRs), recorded in the same listeners, were used to predict FFRs and test the long-held assumption that the sustained potential reflects a series of overlapping onset responses. Results showed that FFRs were maximal at frontocentral scalp locations with obliquely oriented sources from putative generators in the midbrain (i.e., upper brainstem). Comparisons between derived and actual recordings revealed the FFR is not a series of repeated ABR wavelets and thus, represents a functionally distinct brainstem response. FFRs recorded at temporal electrode sites showed larger amplitudes and contained higher frequency components than vertex channels (Fz, Cz) suggesting that FFRs measured near the mastoid are generated more peripherally (auditory nerve) than measurements at frontocentral scalp locations. Furthermore, this reveals the importance of choice in reference electrode location for FFR interpretation. Our findings provide non-invasive evidence that (i) FFRs reflect sustained neural activity whose sources are consistent with rostral brainstem generators and (ii) FFRs are functionally distinct from the onset ABR response.

Consequences of traumatic brain injury for human vergence dynamics.

Purpose: Traumatic brain injury involving loss of consciousness has focal effects in the human brainstem, suggesting that it may have particular consequences for eye movement control. This hypothesis was investigated by measurements of vergence eye movement parameters.Methods: Disparity vergence eye movements were measured for a population of 123 normally sighted individuals, 26 of whom had suffered diffuse traumatic brain injury (dTBI) in the past, while the remainder served as controls. Vergence tracking responses were measured to sinusoidal disparity modulation of a random-dot field. Disparity vergence step responses were characterized in terms of their dynamic parameters separately for the convergence and divergence directions.Results: The control group showed notable differences between convergence and divergence dynamics. The dTBI group showed significantly abnormal vergence behavior on many of the dynamic parameters.Conclusion: The results support the hypothesis that occult injury to the oculomotor control system is a common residual outcome of dTBI.

Neuroglobin Expression in the Mammalian Auditory System.

The energy-yielding pathways that provide the large amounts of metabolic energy required by inner ear sensorineural cells are poorly understood. Neuroglobin (Ngb) is a neuron-specific hemoprotein of the globin family, which is suggested to be involved in oxidative energy metabolism. Here, we present quantitative real-time reverse transcription PCR, in situ hybridization, immunohistochemical, and Western blot evidence that neuroglobin is highly expressed in the mouse and rat cochlea. For primary cochlea neurons, Ngb expression is limited to the subpopulation of type I spiral ganglion cells, those which innervate inner hair cells, while the subpopulation of type II spiral ganglion cells which innervate the outer hair cells do not express Ngb. We further investigated Ngb distribution in rat, mouse, and human auditory brainstem centers, and found that the cochlear nuclei and superior olivary complex (SOC) also express considerable amounts of Ngb. Notably, the majority of olivocochlear neurons, those which provide efferent innervation of outer hair cells as identified by neuronal tract tracing, were Ngb-immunoreactive. We also observed that neuroglobin in the SOC frequently co-localized with neuronal nitric oxide synthase, the enzyme responsible for nitric oxide production. Our findings suggest that neuroglobin is well positioned to play an important physiologic role in the oxygen homeostasis of the peripheral and central auditory nervous system, and provides the first evidence that Ngb signal differentiates the central projections of the inner and outer hair cells.

Auditory brainstem's sensitivity to human voices

Differentiating between voices is a basic social skill humans acquire early in life. The current study aimed to understand the subcortical mechanisms of voice processing by focusing on the two most important acoustical voice features: the fundamental frequency (F0) and harmonics. We measured frequency following responses in a group of young adults to a naturally produced speech syllable under two linguistic contexts: same-syllable and multiple-syllable. Compared to the same-syllable context, the multiple-syllable context contained more speech cues to aid voice processing. We analyzed the magnitude of the response to the F0 and harmonics between same-talker and multiple-talker conditions within each linguistic context. Results establish that the human auditory brainstem is sensitive to different talkers as shown by enhanced harmonic responses under the multiple-talker compared to the same-talker condition, when the stimulus stream contained multiple syllables. This study thus provides the first electrophysiological evidence of the auditory brainstem's sensitivity to human voices.

Continued maturation of the click-evoked auditory brainstem response in preschoolers.

Click-evoked auditory brainstem responses (ABRs) are a valuable tool for probing auditory system function and development. Although it has long been thought that the human auditory brainstem is fully mature by age 2 yr, recent evidence indicates a prolonged developmental trajectory. The purpose of this study was to determine the time course of ABR maturation in a preschool population and fill a gap in the knowledge of development. Using a cross-sectional design, we investigated the effect of age on absolute latencies, interwave latencies, and amplitudes (waves I, III, V) of the click-evoked ABR. A total of 71 preschoolers (ages 3.12-4.99 yr) participated in the study. All had normal peripheral auditory function and IQ. ABRs to a rarefaction click stimulus presented at 31/sec and 80 dB SPL (73 dB nHL) were recorded monaurally using clinically-standard recording and filtering procedures while the participant sat watching a movie. Absolute latencies, interwave latencies, and amplitudes were then correlated to age. Developmental changes were restricted to absolute latencies. Wave V latency decreased significantly with age, whereas wave I and III latencies remained stable, even in this restricted age range. The ABR does not remain static after age 2 yr, as seen by a systematic decrease in wave V latency between ages 3 and 5 yr. This finding suggests that the human brainstem has a continued developmental time course during the preschool years. Latency changes in the age 3-5 yr range should be considered when using ABRs as a metric of hearing health.

Structural and functional connectivity mapping of the vestibular circuitry from human brainstem to cortex.

Structural and functional interconnections of the bilateral central vestibular network have not yet been completely delineated. This includes both ipsilateral and contralateral pathways and crossing sites on the way from the vestibular nuclei via the thalamic relay stations to multiple "vestibular cortex" areas. This study investigated "vestibular" connectivity in the living human brain in between the vestibular nuclei and the parieto-insular vestibular cortex (PIVC) by combined structural and functional connectivity mapping using diffusion tensor imaging and functional connectivity magnetic resonance imaging in 24 healthy right-handed volunteers. We observed a congruent functional and structural link between the vestibular nuclei and the ipsilateral and contralateral PIVC. Five separate and distinct vestibular pathways were identified: three run ipsilaterally, while the two others cross either in the pons or the midbrain. Two of the ipsilateral projections run through the posterolateral or paramedian thalamic subnuclei, while the third bypasses the thalamus to reach the inferior part of the insular cortex directly. Both contralateral pathways travel through the posterolateral thalamus. At the cortical level, the PIVC regions of both hemispheres with a right hemispherical dominance are interconnected transcallosally through the antero-caudal splenium. The above-described bilateral vestibular circuitry in its entirety takes the form of a structure of a rope ladder extending from the brainstem to the cortex with three crossings in the brainstem (vestibular nuclei, pons, midbrain), none at thalamic level and a fourth cortical crossing through the splenium of the corpus callosum.

From Nissl stains to modern concepts of brainstem function

For most neurologists, the name Olszewski is associated with the 1964 seminal paper describing progressive supranuclear palsy (PSP), which was co-authored with Drs John C. Steele and J. Clifford Richardson of Toronto (Steele et al. , 1964). However, an earlier, important contribution by Dr Olszewski was his collaboration with Donald Baxter to produce their atlas, Cytoarchitecture of the Human Brainstem (1954). A third, revised and extended, edition of the atlas has now been provided by Professors Jean Buttner-Ennever and Anja Horn, of the University of Munich. Before describing what this new edition offers to neurologists and neuroscientists, a short historical summary of Olszewski, the evolution of his ideas and those of his successors concerning the brainstem—and especially the reticular formation—may help readers to understand how this atlas mirrors the development of current concepts in the clinical neurosciences. Jerzy (George) Olszewski grew up and attended medical school in what is now Vilnius, Lithuania and, during World War II, survived first Russian, and then German, invasions of his town by working ‘underground’ in a civilian army hospital (Baxter et al. , 1987). Drawing on close, long-standing ties between academics at Vilnius and the Vogt Brain Research Institute in Germany, Olszewski was able, in 1943, to obtain a position as assistant to Oskar and Cecile Vogt. The Vogts greatly influenced him and got him started on studying the brainstem reticular formation. After the war, economic circumstance forced Olszewski to move, and Oskar Vogt wrote to Wilder Penfield, who was eventually persuaded to accept him as a fellow at Montreal Neurological Institute. In collaboration with Donald Baxter (then …

Perceptual consequences of "hidden" hearing loss.

Dramatic results from recent animal experiments show that noise exposure can cause a selective loss of high-threshold auditory nerve fibers without affecting absolute sensitivity permanently. This cochlear neuropathy has been described as hidden hearing loss, as it is not thought to be detectable using standard measures of audiometric threshold. It is possible that hidden hearing loss is a common condition in humans and may underlie some of the perceptual deficits experienced by people with clinically normal hearing. There is some evidence that a history of noise exposure is associated with difficulties in speech discrimination and temporal processing, even in the absence of any audiometric loss. There is also evidence that the tinnitus experienced by listeners with clinically normal hearing is associated with cochlear neuropathy, as measured using Wave I of the auditory brainstem response. To date, however, there has been no direct link made between noise exposure, cochlear neuropathy, and perceptual difficulties. Animal experiments also reveal that the aging process itself, in the absence of significant noise exposure, is associated with loss of auditory nerve fibers. Evidence from human temporal bone studies and auditory brainstem response measures suggests that this form of hidden loss is common in humans and may have perceptual consequences, in particular, regarding the coding of the temporal aspects of sounds. Hidden hearing loss is potentially a major health issue, and investigations are ongoing to identify the causes and consequences of this troubling condition.

Georg Büchner, Sigmund Freud and the "Schädelnerven" (cranial nerves) - research on the brain and soul in the 19th century.

One of the authors' encounter with one of Sigmund Freud's original works about the anatomy of the human brain stem and his interest in the scientist, anatomist, philosopher, writer and revolutionary Georg Büchner led to re-examination and review of the original writings of two major 19th century protagonists of brain anatomy research. The aim of the authors is to highlight the achievements of both Freud and Büchner in the field of comparative brain morphology. The medical and philosophical publications of Georg Büchner were reviewed with reference to the historical-critical edition of his complete works and writings (the so-called Marburg edition). Evaluation of the neuroanatomical achievements of Sigmund Freud was based on a summary of his publications and also partially on his autobiographical writings. After careful review of their publications both Freud and Büchner should be acknowledged as brain scientists focusing particularly on comparative morphology. Both chose fish as the subject of their macroscopic (Büchner) and microscopic (Freud) neuroanatomical studies, and both cut across their own language and cultural space by continuing their work in France. In interpreting their findings both were influenced by their respective contemporary methodological schools of thought. Büchner became a soul scientist/psychologist by turning to the writing of literary texts, heralding the end of his idealistic and metaphysical interpretation of life. Likewise, Freud increasingly devoted himself to the destiny of man and his "conditio humana," eventually turning away from anatomical brain research. Review of the biographies and medical-scientific, as well as philosophical publications, of Georg Büchner and Sigmund Freud reveal striking parallels between the two researchers in addition to common insights that have generally been ignored or only marginally addressed in the past. Both should be appreciated and remembered as forerunners of today's neuroscientific community.

Adeno-associated virus type 2 wild-type and vector-mediated genomic integration profiles of human diploid fibroblasts analyzed by third-generation PacBio DNA sequencing.

Genome-wide analysis of adeno-associated virus (AAV) type 2 integration in HeLa cells has shown that wild-type AAV integrates at numerous genomic sites, including AAVS1 on chromosome 19q13.42. Multiple GAGY/C repeats, resembling consensus AAV Rep-binding sites are preferred, whereas rep-deficient AAV vectors (rAAV) regularly show a random integration profile. This study is the first study to analyze wild-type AAV integration in diploid human fibroblasts. Applying high-throughput third-generation PacBio-based DNA sequencing, integration profiles of wild-type AAV and rAAV are compared side by side. Bioinformatic analysis reveals that both wild-type AAV and rAAV prefer open chromatin regions. Although genomic features of AAV integration largely reproduce previous findings, the pattern of integration hot spots differs from that described in HeLa cells before. DNase-Seq data for human fibroblasts and for HeLa cells reveal variant chromatin accessibility at preferred AAV integration hot spots that correlates with variant hot spot preferences. DNase-Seq patterns of these sites in human tissues, including liver, muscle, heart, brain, skin, and embryonic stem cells further underline variant chromatin accessibility. In summary, AAV integration is dependent on cell-type-specific, variant chromatin accessibility leading to random integration profiles for rAAV, whereas wild-type AAV integration sites cluster near GAGY/C repeats. Adeno-associated virus type 2 (AAV) is assumed to establish latency by chromosomal integration of its DNA. This is the first genome-wide analysis of wild-type AAV2 integration in diploid human cells and the first to compare wild-type to recombinant AAV vector integration side by side under identical experimental conditions. Major determinants of wild-type AAV integration represent open chromatin regions with accessible consensus AAV Rep-binding sites. The variant chromatin accessibility of different human tissues or cell types will have impact on vector targeting to be considered during gene therapy.

Peak I of the human auditory brainstem response results from the somatic regions of type I spiral ganglion cells: Evidence from computer modeling

Early neural responses to acoustic signals can be electrically recorded as a series of waves, termed the auditory brainstem response (ABR). The latencies of the ABR waves are important for clinical and neurophysiological evaluations. Using a biophysical model of transmembrane currents along spiral ganglion cells, we show that in human (i) the non-myelinated somatic regions of type I cells, which innervate inner hair cells, predominantly contribute to peak I, (ii) the supra-strong postsynaptic stimulating current (400 pA) and transmembrane currents of the myelinated peripheral axons of type I cells are an order smaller; such postsynaptic currents correspond to the short latencies of a small recordable ABR peak I’, (iii) the ABR signal involvement of the central axon of bipolar type I cells is more effective than their peripheral counterpart as the doubled diameter causes larger transmembrane currents and a larger spike dipole-length, (iv) non-myelinated fibers of type II cells which innervate the outer hair cells generate essentially larger transmembrane currents but their ABR contribution is small because of the small ratio type II/type I cells, low firing rates and a short dipole length of spikes propagating slowly in non-myelinated fibers. Using a finite element model of a simplified head, peaks In and II (where In is the negative peak after peak I) are found to be stationary potentials when volleys of spikes cross the external electrical conductivity barrier at the bone&dura/CSF and at the CSF/brainstem interface whereas peaks I’ and I may be generated by strong local transmembrane currents as postsynaptic events at the distal ending and the soma region of type I cells, respectively. All simulated human inter-peak times (I–I′, II–I, In–I) are close to published data.