Tom P. Franken

In vivo coincidence detection in mammalian sound localization generates phase delays

Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay that offsets the acoustic delay and determines neural tuning. We used in vivo patch-clamp recordings of binaural neurons in the Mongolian gerbil and pharmacological manipulations to directly compare neuronal input to output and to separate excitation from inhibition. Our results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process, but is instead shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can therefore be combined in a single operation.

Coincidence detection in the medial superior olive: mechanistic implications of an analysis of input spiking patterns

Coincidence detection by binaural neurons in the medial superior olive underlies sensitivity to interaural time difference (ITD) and interaural correlation (ρ). It is unclear whether this process is akin to a counting of individual coinciding spikes, or rather to a correlation of membrane potential waveforms resulting from converging inputs from each side. We analyzed spike trains of axons of the cat trapezoid body (TB) and auditory nerve (AN) in a binaural coincidence scheme. ITD was studied by delaying “ipsi-” vs. “contralateral” inputs; ρ was studied by using responses to different noises. We varied the number of inputs; the monaural and binaural threshold and the coincidence window duration. We examined physiological plausibility of output “spike trains” by comparing their rate and tuning to ITD and ρ to those of binaural cells. We found that multiple inputs are required to obtain a plausible output spike rate. In contrast to previous suggestions, monaural threshold almost invariably needed to exceed binaural threshold. Elevation of the binaural threshold to values larger than 2 spikes caused a drastic decrease in rate for a short coincidence window. Longer coincidence windows allowed a lower number of inputs and higher binaural thresholds, but decreased the depth of modulation. Compared to AN fibers, TB fibers allowed higher output spike rates for a low number of inputs, but also generated more monaural coincidences. We conclude that, within the parameter space explored, the temporal patterns of monaural fibers require convergence of multiple inputs to achieve physiological binaural spike rates; that monaural coincidences have to be suppressed relative to binaural ones; and that the neuron has to be sensitive to single binaural coincidences of spikes, for a number of excitatory inputs per side of 10 or less. These findings suggest that the fundamental operation in the mammalian binaural circuit is coincidence counting of single binaural input spikes.

Variations on a Dexterous theme: peripheral time-intensity trading

Sound pressure level changes can affect the timing of spiketrains. Timing of spiketrains is critical for sensitivity to interaural timing differences (ITDs). Interaural level differences (ILDs) can therefore affect the ITD cue. It has been hypothesized that ILDs may be coded indirectly through a peripheral conversion of level to time (but it should be cautioned that the changes in phase with SPL in low-CF AN fibers of the cat are more complicated) (Jeffress, L.A., 1948. A place theory of sound localization. J. Comp. Physiol. Psychol. 41, 35-39). We tested this conversion by recording from auditory nerve fibers to broadband noise at different SPLs. For each fiber, correlograms were constructed to compare timing to fine-structure across SPLs. We find generally a decrease in the time delay between spikes and the stimulus with increasing SPL. However, the magnitudes of the shift in time are surprisingly small, and dependent on characteristic frequency (CF): the largest shifts are approximately 10 micros/dB and occur at the lowest CFs. Nevertheless, the effects of level on spike timing are systematic and of a magnitude to which the binaural system is sensitive. Thus, even though the results indicate that ILD is not traded for ITD in a simple way, the possibility that low-frequency ILDs affect the binaural percept via a peripheral level-to-time conversion cannot be excluded.

Neural tuning matches frequency-dependent time differences between the ears

The time it takes a sound to travel from source to ear differs between the ears and creates an interaural delay. It varies systematically with spatial direction and is generally modeled as a pure time delay, independent of frequency. In acoustical recordings, we found that interaural delay varies with frequency at a fine scale. In physiological recordings of midbrain neurons sensitive to interaural delay, we found that preferred delay also varies with sound frequency. Similar observations reported earlier were not incorporated in a functional framework. We find that the frequency dependence of acoustical and physiological interaural delays are matched in key respects. This suggests that binaural neurons are tuned to acoustical features of ecological environments, rather than to fixed interaural delays. Using recordings from the nerve and brainstem we show that this tuning may emerge from neurons detecting coincidences between input fibers that are mistuned in frequency. DOI: http://dx.doi.org/10.7554/eLife.06072.001

In vivo Whole-Cell Recordings Combined with Electron Microscopy Reveal Unexpected Morphological and Physiological Properties in the Lateral Nucleus of the Trapezoid Body in the Auditory Brainstem

The lateral nucleus of the trapezoid body (LNTB) is a prominent nucleus in the superior olivary complex in mammals including humans. Its physiology in vivo is poorly understood due to a paucity of recordings. It is thought to provide a glycinergic projection to the medial superior olive (MSO) with an important role in binaural processing and sound localization. We combined in vivo patch clamp recordings with labeling of individual neurons in the Mongolian gerbil. Labeling of the recorded neurons allowed us to relate physiological properties to anatomy at the light and electron microscopic level. We identified a population of quite dorsally located neurons with surprisingly large dendritic trees on which most of the synaptic input impinges. In most neurons, one or more of these dendrites run through and are then medial to the MSO. These neurons were often binaural and could even show sensitivity to interaural time differences (ITDs) of stimulus fine structure or envelope. Moreover, a subpopulation showed enhanced phase-locking to tones delivered in the tuning curve tail. We propose that these neurons constitute the gerbil main LNTB (mLNTB). In contrast, a smaller sample of neurons was identified that was located more ventrally and that we designate to be in posteroventral LNTB (pvLNTB). These cells receive large somatic excitatory terminals from globular bushy cells. We also identified previously undescribed synaptic inputs from the lateral superior olive. pvLNTB neurons are usually monaural, display a primary-like-with-notch response to ipsilateral short tones at CF and can phase-lock to low frequency tones. We conclude that mLNTB contains a population of neurons with extended dendritic trees where most of the synaptic input is found, that can show enhanced phase-locking and sensitivity to ITD. pvLNTB cells, presumed to provide glycinergic input to the MSO, get large somatic globular bushy synaptic inputs and are typically monaural with short tone responses similar to their primary input from the cochlear nucleus.

The Interaural Time Difference Pathway: a Comparison of Spectral Bandwidth and Correlation Sensitivity at Three Anatomical Levels

ABSTRACTTemporal differences between the two ears are critical for spatial hearing. They can be described along axes of interaural time difference (ITD) and interaural correlation, and their processing starts in the brainstem with the convergence of monaural pathways which are tuned in frequency and which carry temporal information. In previous studies, we examined the bandwidth (BW) of frequency tuning at two stages: the auditory nerve (AN) and inferior colliculus (IC), and showed that BW depends on characteristic frequency (CF) but that there is no difference in the mean BW of these two structures when measured in a binaural, temporal framework. This suggested that there is little frequency convergence in the ITD pathway between AN and IC and that frequency selectivity determined by the cochlear filter is preserved up to the IC. Unexpectedly, we found that AN and IC neurons can be similar in CF and BW, yet responses to changes in interaural correlation in the IC were different than expected from coincidence patterns (“pseudo-binaural” responses) in the AN. To better understand this, we here examine the responses of bushy cells, which provide monaural inputs to binaural neurons. Using broadband noise, we measured BW and correlation sensitivity in the cat trapezoid body (TB), which contains the axons of bushy cells. This allowed us to compare these two metrics at three stages in the ITD pathway. We found that BWs in the TB are similar to those in the AN and IC. However, TB neurons were found to be more sensitive to changes in stimulus correlation than AN or IC neurons. This is consistent with findings that show that TB fibers are more temporally precise than AN fibers, but is surprising because it suggests that the temporal information available monaurally is not fully exploited binaurally.

Principal cells of the brainstem's interaural sound level detector are temporal differentiators rather than integrators

The brainstem’s lateral superior olive (LSO) is thought to be crucial for localizing high-frequency sounds by coding interaural sound level differences (ILD). Its neurons weigh contralateral inhibition against ipsilateral excitation, making their firing rate a function of the azimuthal position of a sound source. Since the very first in vivo recordings, LSO principal neurons have been reported to give sustained and temporally integrating ‘chopper’ responses to sustained sounds. Neurons with transient responses were observed but largely ignored and even considered a sign of pathology. Using the Mongolian gerbil as a model system, we have obtained the first in vivo patch clamp recordings from labeled LSO neurons and find that principal LSO neurons, the most numerous projection neurons of this nucleus, only respond at sound onset and show fast membrane features suggesting an importance for timing. These results provide a new framework to interpret previously puzzling features of this circuit.

Posterior reversible encephalopathy syndrome in multiple system atrophy.

Posterior reversible encephalopathy syndrome (PRES) is characterized by usually reversible vasogenic brain edema predominantly in the bilateral parieto-occipital regions, and presents with (sub)acute headache, confusion, visual symptoms or seizures. PRES typically arises from severe blood pressure fluctuations or abrupt hypertension, but can also occur in other settings such as renal failure or use of cytotoxic drugs [1]. Patients with multiple system atrophy (MSA) often have widely fluctuating blood pressures [2]. Nevertheless, there is only one report of a patient with MSA who developed PRES; this case was tentatively attributed to use of the sympathomimetic agent midodrine [3]. Here, we report a patient with MSA and severe blood pressure fluctuations who developed PRES without exposure to sympathomimetic drugs. A 51-year-old physician developed urinary incontinence in 2008 and impotence, motor slowing, dysarthria and balance problems in 2012. Clinical exam in 2013 showed moderate, symmetrical parkinsonism. Brain MRI was negative. 123I-FP-CIT SPECT showed bilaterally reduced dopamine transporter binding. Treatment with levodopa (200 mg qid) and pramipexole (2.1 mg daily) had only limited effect. He fulfilled the diagnostic criteria for probable MSA with predominant parkinsonism (MSA-P) [4]. In 2014 he developed orthostatic hypotension, which led to pramipexole cessation and reduction of levodopa to 100 mg qid. Yet, his orthostatic hypotension continued to worsen, and by 2015 he had almost daily syncopes. In January 2015 he started taking fludrocortisone (100 mg daily), with a favorable effect on the frequency of syncopes. He started systematically recording his blood pressure and documented severe fluctuations (e.g. from 215/113 mmHg to 73/48 mmHg within 2 hours). His speech continued to deteriorate and he became dependent on a rollator for ambulation. In September 2015 he had a brief syncope with a blood pressure of 88/60 mmHg. After regaining consciousness he initially l, and 80 minutes later blood pressure was 205/ Hg. Two hours after the syncope he developed blurred vision and confusion without headache. Upon hospital admission (3.5 hours after the syncope) blood pressure was 195/117 mmHg. During the neurological exam he developed a generalized tonicclonic seizure. IV anti-epileptics were administered, he was sedated and intubated and received nicardipine IV for several hours to control his hypertension. On the next day, after extubation and cessation of sedation, he was well-oriented and denied visual symptoms. MRI showed bilateral diffuse FLAIRhyperintense parieto-occipital and cerebellar lesions (Fig. 1A,B), leading to a diagnosis of PRES. Fludrocortisone was stopped and levodopa reduced to 50 mg qid. MRI nine days after admission showed resolution of the lesions (Fig. 1C,D), and he recovered from the PRES episode without clinical sequelae. His blood pressure remained very unstable. Twenty-four hour blood pressure monitoring 20 days after fludrocortisone cessation still showed severe fluctuations (ranging from 211/136 mmHg to 66/44 mmHg). Our patient and the other reported MSA patient with PRES [3] both used medication to increase blood pressure. The development of PRES may have been a complication of these treatments to raise blood pressure, although this is uncertain. Severe blood pressure fluctuations are common in MSA patients, who may therefore be at increased risk of PRES. We suspect that PRES may be underrecognized in MSA, because typical clinical manifestations of PRES such as headache, blurred vision and confusion can be mistaken for symptoms of low blood pressure or oculomotor disturbance in MSA patients.

A small leak will sink the brain: targeted C1-C2 patching.

BACKGROUND Spontaneous intracranial hypotension syndrome results from spontaneous spinal cerebrospinal fluid (CSF) leaks. The first treatment of choice consists of lumbar epidural blood patching. If this fails, further imaging is mandatory to explore the possibility of targeted therapy. CASE DESCRIPTION We describe a case of a 50-year-old woman who developed spontaneous intracranial hypotension after minor blunt cervical trauma, complicated with bilateral subdural hematomas. Two lumbar epidural blood patches were unsuccessful. Magnetic resonance imaging with intrathecal gadolinium revealed a CSF leak at the C1-C2 level. A targeted blood patch via a percutaneous high thoracic epidural approach was performed, and symptoms disappeared in the immediate postoperative period with a regression of the subdural hematomas on subsequent imaging. CONCLUSIONS A targeted epidural blood patch using an epidural catheter represents an elegant approach to a CSF leak at the C1-C2 region and can be successful in treating patients with severe intracranial hypotension syndrome.

In-vivo intra-cellular characterization of “OFF” responses in the superior para-olivary nucleus

The superior para-olivary nucleus (SPN) is an auditory-brainstem OFF channel. Typically, SPN neurons are inhibited during sound presentation and fire at sound offset. Release from sound-induced inhibitory potentials is the hypothesized mechanism, but this has not previously been directly observed in vivo. We obtained in vivo axonal recordings from 33 SPN neurons in the chinchilla, and patch recordings from 17 SPN cell bodies in the Mongolian gerbil. We retrieved several cells anatomically by labeling with biocytin or neurobiotin. Labeled SPN neurons had large dendritic trees, and axons heading into the lateral lemniscus. Their responses typically showed offset spiking to contralateral, and sometimes to ipsilateral stimulation. Spikes in response to amplitude-modulated tones were highly synchronized, up to hundreds of Hz (vector strength >0.9). Some SPN neurons were ITD sensitive, either to envelope or low-frequency fine-structure components. Patch-clamp recording allowed us to study sub-threshold potentia...