[Differentiating cochlear synaptopathies into different hearing disorders]. / Differenzierung cochleärer Synaptopathien in verschiedene Hörstörungen.

Due to demographic change and altered recreational behavior, a rapid increase in hearing deficits is expected in the next 20-30 years. Consequently, the risk of age-related loss of speech discrimination, tinnitus, hyperacusis, or-as recently shown-dementia, will also increase. There are increasing indications that the loss of specific hearing fibers in humans and animals is involved in various hearing disorders. This fiber loss can be caused by cochlear synaptopathy or deafferentation and does not necessarily lead to clinically measurable threshold changes. Animal experiments have shown that reduced auditory nerve activity due to acoustic trauma or aging can be centrally compensated by disproportionately elevated and faster auditory brainstem responses (ABR). The analysis of the suprathreshold amplitudes of auditory evoked brain stem potentials and their latency in combination with non-invasive imaging techniques such as magnetic resonance imaging can help to identify the central compensatory ability of subjects and to assign defined hearing deficits.

Neurofeedback Training of Gamma Oscillations in Monkey Primary Visual Cortex.

In humans, neurofeedback (NFB) training has been used extensively and successfully to manipulate brain activity. Feedback signals were derived from EEG, fMRI, MEG, and intracranial recordings and modifications were obtained of the BOLD signal, of the power of oscillatory activity in distinct frequency bands and of single unit activity. The purpose of the present study was to examine whether neuronal activity could also be controlled by NFB in early sensory cortices whose activity is thought to be influenced mainly by sensory input rather than volitional control. We trained 2 macaque monkeys to enhance narrow band gamma oscillations in the primary visual cortex by providing them with an acoustic signal that reflected the power of gamma oscillations in a preselected band and rewarding increases of the feedback signal. Oscillations were assessed from local field potentials recorded with chronically implanted microelectrodes. Both monkeys succeeded to raise gamma activity in the absence of visual stimulation in the selected frequency band and at the site from which the NFB signal was derived. This suggests that top-down signals are not confined to just modulate stimulus induced responses but can actually drive or facilitate the gamma generating microcircuits even in a primary sensory area.

Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome.

BACKGROUND: Gastrointestinal symptoms are common in the postural orthostatic tachycardia syndrome (POTS). However, few studies have evaluated gastrointestinal transit in POTS. Our primary objectives were to evaluate gastrointestinal emptying and the relationship with autonomic dysfunctions in POTS. METHODS: We reviewed the complete medical records of all patients aged 18 years and older with POTS diagnosed by a standardized autonomic reflex screen who also had a scintigraphic assessment of gastrointestinal transit at Mayo Clinic Rochester between 1998 and 2012. Associations between specific gastric emptying and autonomic (i.e., cardiovagal, adrenergic, and sudomotor) disturbances were evaluated. KEY RESULTS: Among 163 patients (140 women, mean [± SEM] age 30 [± 1] years), 55 (34%) had normal, 30 (18%) had delayed, and 78 (48%) had rapid gastric emptying. Fifty-eight patients (36%) had clinical features of physical deconditioning, which was associated (p = 0.02) with rapid gastric emptying. Associations with delayed gastric emptying included vomiting, which was more common (p < 0.003), and anxiety or depression, which was less common (p = 0.02). The tilt-associated increase in heart rate and reduction in systolic BP at 1 min was associated (p < 0.05), being greater in patients with delayed gastric emptying. CONCLUSIONS & INFERENCES: Two-thirds of patients with POTS and GI symptoms had abnormal, most frequently rapid gastric emptying. Except for more severe adrenergic impairment in patients with delayed gastric emptying, the pattern of autonomic dysfunction did not discriminate among gastric emptying groups. Further studies are necessary to ascertain whether extravascular volume depletion and/or deconditioning contribute to POTS in patients with gastrointestinal symptoms.

Saturated ablation in metal hydrides and acceleration of protons and deuterons to keV energies with a soft-x-ray laser.

Studies of materials under extreme conditions have relevance to a broad area of research, including planetary physics, fusion research, materials science, and structural biology with x-ray lasers. We study such extreme conditions and experimentally probe the interaction between ultrashort soft x-ray pulses and solid targets (metals and their deuterides) at the FLASH free-electron laser where power densities exceeding 10(17) W/cm(2) were reached. Time-of-flight ion spectrometry and crater analysis were used to characterize the interaction. The results show the onset of saturation in the ablation process at power densities above 10(16) W/cm(2). This effect can be linked to a transiently induced x-ray transparency in the solid by the femtosecond x-ray pulse at high power densities. The measured kinetic energies of protons and deuterons ejected from the surface reach several keV and concur with predictions from plasma-expansion models. Simulations of the interactions were performed with a nonlocal thermodynamic equilibrium code with radiation transfer. These calculations return critical depths similar to the observed crater depths and capture the transient surface transparency at higher power densities.

Stabilization of visual responses through cholinergic activation.

Neuronal processing of sensory information requires that rapidly changing synaptic inputs are continuously transformed into action potentials. Variability of spike firing is generally considered as noise and might therefore interfere with the reliability of synaptic transmission in sensory systems. In a system in which the number of spikes is a variable that determines the quality of neuronal transmission, variability of spike counts is a paradoxical attribute. In contrast, in a system in which precisely correlated spike firing can influence synaptic integration, response variability might be used as an additional mechanism for coding information. As acetylcholine has been shown to reduce spike-frequency adaptation and enhance gamma frequency (21-70 Hz) oscillations, we set out to study the influence of cholinergic modulation on the variability of spike counts and gamma oscillations. Iontophoretic application of carbachol, a cholinergic agonist, in cat primary visual cortex or electrical stimulation of the mesencephalic reticular formation reduced the spike count variability and stabilized gamma frequency oscillations of visually induced responses. Response stabilization was correlated with enhancement of gamma-frequency oscillations but not with averaged firing rates. Lowering variability of sensory responses might be a mechanism to stabilize and improve reliability of neuronal transmission. Cholinergic activation may therefore influence the efficacy of neuronal transmission by modulating the precise timing of neuronal responses.

Long-term effects of a plant-based dietary portfolio of cholesterol-lowering foods on blood pressure.

OBJECTIVE: To determine the effect on blood pressure of dietary advice to consume a combination of plant-based cholesterol-lowering foods (dietary portfolio). METHODS: For 1 year, 66 hyperlipidemic subjects were prescribed diets high in plant sterols (1.0 g/1000 kcal), soy protein (22.5 g/1000 kcal), viscous fibers (10 g/1000 kcal) and almonds (22.5 g/1000 kcal). There was no control group. Seven-day diet record, blood pressure and body weight were monitored initially monthly and later at 2-monthly intervals throughout the study. RESULTS: Fifty subjects completed the 1-year study. When the last observation was carried forward for non-completers (n=9) or those who changed their blood pressure medications (n=7), a small mean reduction was seen in body weight 0.7+/-0.3 kg (P=0.036). The corresponding reductions from baseline in systolic and diastolic blood pressure at 1 year (n=66 subjects) were -4.2+/-1.3 mm Hg (P=0.002) and -2.3+/-0.7 mm Hg (P=0.001), respectively. Blood pressure reductions occurred within the first 2 weeks, with stable blood pressures 6 weeks before and 4 weeks after starting the diet. Diastolic blood pressure reduction was significantly related to weight change (r=0.30, n=50, P=0.036). Only compliance with almond intake advice related to blood pressure reduction (systolic: r=-0.34, n=50, P=0.017; diastolic: r=-0.29, n=50, P=0.041). CONCLUSIONS: A dietary portfolio of plant-based cholesterol-lowering foods reduced blood pressure significantly, related to almond intake. The dietary portfolio approach of combining a range of cholesterol-lowering plant foods may benefit cardiovascular disease risk both by reducing serum lipids and also blood pressure.

A spatio-temporal interaction on the apparent motion trace.

During the perception of apparent motion, activity along the apparent motion trace has been found in the primary visual cortex. It has been hypothesized that this activity interferes with stimuli presented on the apparent motion trace ("motion masking"). We investigated whether this perceptual interference varies with regard to the trajectory of a moving object token in a detection task. We found a general decrease of detectability of targets presented on the trace. Surprisingly, targets presented in time with the trajectory were detected significantly more often than targets which appeared out of time. We relate this finding to a spatio-temporally specific prediction of visual events along the apparent motion trace.

Tinnitus behavior and hearing function correlate with the reciprocal expression patterns of BDNF and Arg3.1/arc in auditory neurons following acoustic trauma.

The molecular changes following sensory trauma and the subsequent response of the CNS are poorly understood. We focused on finding a molecular tool for monitoring the features of excitability which occur following acoustic trauma to the auditory system. Of particular interest are genes that alter their expression pattern during activity-induced changes in synaptic efficacy and plasticity. The expression of brain-derived neurotrophic factor (BDNF), the activity-dependent cytoskeletal protein (Arg3.1/arc), and the immediate early gene c-Fos were monitored in the peripheral and central auditory system hours and days following a traumatic acoustic stimulus that induced not only hearing loss but also phantom auditory perception (tinnitus), as shown in rodent animal behavior models. A reciprocal responsiveness of activity-dependent genes became evident between the periphery and the primary auditory cortex (AI): as c-Fos and BDNF exon IV expression was increased in spiral ganglion neurons, Arg3.1/arc and (later on) BDNF exon IV expression was reduced in AI. In line with studies indicating increased spontaneous spike activity at the level of the inferior colliculus (IC), an increase in BDNF and GABA-positive neurons was seen in the IC. The data clearly indicate the usefulness of Arg3.1/arc and BDNF for monitoring trauma-induced activity changes and the associated putative plasticity responses in the auditory system.

Retinotopic effects during spatial audio-visual integration.

The successful integration of visual and auditory stimuli requires information about whether visual and auditory signals originate from corresponding places in the external world. Here we report crossmodal effects of spatially congruent and incongruent audio-visual (AV) stimulation. Visual and auditory stimuli were presented from one of four horizontal locations in external space. Seven healthy human subjects had to assess the spatial fit of a visual stimulus (i.e. a gray-scaled picture of a cartoon dog) and a simultaneously presented auditory stimulus (i.e. a barking sound). Functional magnetic resonance imaging (fMRI) revealed two distinct networks of cortical regions that processed preferentially either spatially congruent or spatially incongruent AV stimuli. Whereas earlier visual areas responded preferentially to incongruent AV stimulation, higher visual areas of the temporal and parietal cortex (left inferior temporal gyrus [ITG], right posterior superior temporal gyrus/sulcus [pSTG/STS], left intra-parietal sulcus [IPS]) and frontal regions (left pre-central gyrus [PreCG], left dorsolateral pre-frontal cortex [DLPFC]) responded preferentially to congruent AV stimulation. A position-resolved analysis revealed three robust cortical representations for each of the four visual stimulus locations in retinotopic visual regions corresponding to the representation of the horizontal meridian in area V1 and at the dorsal and ventral borders between areas V2 and V3. While these regions of interest (ROIs) did not show any significant effect of spatial congruency, we found subregions within ROIs in the right hemisphere that showed an incongruency effect (i.e. an increased fMRI signal during spatially incongruent compared to congruent AV stimulation). We interpret this finding as a correlate of spatially distributed recurrent feedback during mismatch processing: whenever a spatial mismatch is detected in multisensory regions (such as the IPS), processing resources are re-directed to low-level visual areas.

Effect on hematologic risk factors for coronary heart disease of a cholesterol reducing diet.

BACKGROUND: A dietary portfolio of cholesterol-lowering ingredients has proved effective in reducing serum cholesterol. However, it is not known whether this dietary combination will also affect hematologic risk factors for coronary heart disease (CHD). Reductions in hematocrit and polymorphonuclear leukocytes have been reported to improve cardiovascular risk. We, therefore, report changes in hematological indices, which have been linked to cardiovascular health, in a 1-year assessment of subjects taking an effective dietary combination (portfolio) of cholesterol-lowering foods. METHODS: For 12 months, 66 hyperlipidemic subjects were prescribed diets high in plant sterols (1.0 g/1000 kcal), soy protein (22.5 g/1000 kcal), viscous fibers (10 g/1000 kcal) and almonds (23 g/1000 kcal). Fifty-five subjects completed the study. RESULTS: Over the 1 year, data on completers indicated small but significant reductions in hemoglobin (-1.5+/-0.6 g/l, P=0.013), hematocrit (-0.007+/-0.002 l/l, P<0.001), red cell number (-0.07+/-0.02 10(9)/l, P<0.001) and neutrophils (-0.34+/-0.13 10(9)/l, P=0.014). Mean platelet volume was also increased (0.16+/-0.07 fl, P=0.033). The increase in red cell osmotic fragility (0.05+/-0.03 g/l, P=0.107) did not reach significance. CONCLUSIONS: These small changes in hematological indices after a cholesterol-lowering diet are in the direction, which would be predicted to reduce CHD risk. Further research is needed to clarify whether the changes observed will contribute directly or indirectly to cardiovascular benefits beyond those expected from reductions previously seen in serum lipids and blood pressure.

Silent adenoma subtype 3 of the pituitary--immunohistochemical and ultrastructural classification: a review of 29 cases.

The silent adenoma subtype 3 (SAS-3) of undetermined cellular derivation is a seemingly nonfunctioning aggressive pituitary tumor with a high recurrence rate. At the time of diagnosis SAS-3s are macro- or giant adenomas particularly aggressive in young individuals, especially women. They are usually associated with mild hyperprolactinemia and are unremarkable by histology. Immunohistochemistry, demonstrating scattered immunoreactivity mostly for GH, PRL, TSH, and alpha-subunit, is not diagnostic. Presently, only TEM permits conclusive diagnosis. Ultrastructurally, the large polar adenoma cells contain abundant RER, masses of SER, extensive multipolar Golgi apparatus, and unevenly clustered mitochondria, displaced by RER and SER, which may show close spatial relationship to RER. Cell membranes often form plexiform interdigitations. Nuclear pleomorphism and nuclear inclusions are common. The 100- to 200-nm secretory granules accumulate heavily in cell processes, which is a hallmark of glycoprotein hormone cell differentiation. The endothelial cells may contain tubuloreticular inclusions. Complete surgical removal of the large often invasive tumors is difficult necessitating postoperative treatment. SAS-3 is sensitive to conventional radiation. Some tumors express somatostatin receptors and respond well to somatostatin analogues, offering long-term control in patients with residual tumor. Possible derivation of SAS-3 from rostral thyrotrophs, a cell type presently known in rodents is contemplated.

Direct comparison of dietary portfolio vs statin on C-reactive protein.

BACKGROUND: 3-Hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) markedly reduce serum cholesterol and have anti-inflammatory effects. The effect of cholesterol-lowering diets on inflammatory biomarkers is less well known. OBJECTIVE: To compare the efficacy of a dietary combination (portfolio) of cholesterol-lowering foods vs a statin in reducing C-reactive protein (CRP) as a biomarker of inflammation linked to increased cardiovascular disease risk. METHODS: In all, 34 hyperlipidemic subjects completed three 1-month treatments as outpatients in random order: a very low-saturated fat diet (control); the same diet with 20 mg lovastatin (statin); and a diet high in plant sterols (1.0 g/1000 kcal), soy protein (21.4 g/1000 kcal), viscous fibers (9.8 g/1000 kcal), and almonds (14 g/1000 kcal) (portfolio). Fasting blood samples were obtained at weeks 0, 2, and 4. RESULTS: Using the complete data, no treatment reduced serum CRP. However, when subjects with CRP levels above the 75th percentile for previously reported studies (> 3.5 mg/l) were excluded, CRP was reduced similarly on both statin, -16.3 +/- 6.7% (n = 23, P = 0.013) and dietary portfolio, -23.8 +/- 6.9% (n = 25, P = 0.001) but not the control, 15.3 +/- 13.6% (n = 28, P = 0.907). The percentage CRP change from baseline on the portfolio treatment (n = 25) was greater than the control (n = 28, P = 0.004) but similar to statin treatment (n = 23, P = 0.349). Both statin and portfolio treatments were similar in reducing CRP and numerically more effective than control but only the change in portfolio was significant after the Bonferroni adjustment. CONCLUSIONS: A combination of cholesterol-lowering foods reduced C-reactive protein to a similar extent as the starting dose of a first-generation statin.

Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies.

BACKGROUND: There are a number of distal and generalized small-fiber neuropathies. The neuropathologic basis is poorly understood as somatic and autonomic C fibers are not usually studied in the same region of the body. OBJECTIVE: To evaluate prospective somatic and autonomic C-fiber function in 11 healthy control subjects and 38 patients with different clinical patterns of neuropathy. METHODS: Distal small-fiber neuropathy (DSFN), peripheral neuropathy (PN), diabetic neuropathy (DN), neuropathic postural tachycardia syndrome (POTS), and idiopathic autonomic neuropathy (IAN) were evaluated. Intraepidermal nerve fiber density was used to evaluate distal somatic C fibers. Both quantitative sudomotor axon reflex test and skin norepinephrine content were measured for the biopsy site to assess distal autonomic C-fiber function. Postganglionic sudomotor, adrenergic, and cardiovagal functions were evaluated by autonomic reflex testing and quantified using a Composite Autonomic Severity Scale. RESULTS: Skin norepinephrine concentration was significantly related to CASS. DN was associated with somatic and autonomic C-fiber impairment with good agreement. POTS was associated with selective distal autonomic deficit. DSFN had combined distal somatic and C-fiber impairment. IAN showed combined and selective distal and generalized autonomic C-fiber impairment. The somatic neuropathies had C-fiber impairment affecting both populations to varying degrees. CONCLUSION: Although a general agreement exists between the loss of somatic C fibers and autonomic deficits, selective involvement occurs for specific autonomic neuropathies.

Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension.

BACKGROUND: Pharmacological treatment of orthostatic hypotension is often limited because of troublesome supine hypertension. OBJECTIVE: To investigate a novel approach to treatment using acetylcholinesterase inhibition, based on the theory that enhanced sympathetic ganglion transmission increases systemic resistance in proportion to orthostatic needs. DESIGN: Prospective open label single dose trial. MATERIAL: 15 patients with neurogenic orthostatic hypotension caused by: multiple system atrophy (n = 7), Parkinson's disease (n = 3), diabetic neuropathy (n = 1), amyloid neuropathy (n = 1), and idiopathic autonomic neuropathy (n = 3). METHODS: Heart rate, blood pressure, peripheral resistance index (PRI), cardiac index, stroke index, and end diastolic index were monitored continuously during supine rest and head up tilt before and one hour after an oral dose of 60 mg pyridostigmine. RESULTS: There was only a modest non-significant increase in supine blood pressure and PRI. In contrast, acetylcholinesterase inhibition significantly increased orthostatic blood pressure and PRI and reduced the fall in blood pressure during head up tilt. Orthostatic heart rate was reduced after the treatment. The improvement in orthostatic blood pressure was associated with a significant improvement in orthostatic symptoms. CONCLUSIONS: Acetylcholinesterase inhibition appears effective in the treatment of neurogenic orthostatic hypotension. Orthostatic symptoms and orthostatic blood pressure are improved, with only modest effects in the supine position. This novel approach may form an alternative or supplemental tool in the treatment of orthostatic hypotension, specially for patients with a high supine blood pressure.

Dynamic predictions: oscillations and synchrony in top-down processing.

Classical theories of sensory processing view the brain as a passive, stimulus-driven device. By contrast, more recent approaches emphasize the constructive nature of perception, viewing it as an active and highly selective process. Indeed, there is ample evidence that the processing of stimuli is controlled by top-down influences that strongly shape the intrinsic dynamics of thalamocortical networks and constantly create predictions about forthcoming sensory events. We discuss recent experiments indicating that such predictions might be embodied in the temporal structure of both stimulus-evoked and ongoing activity, and that synchronous oscillations are particularly important in this process. Coherence among subthreshold membrane potential fluctuations could be exploited to express selective functional relationships during states of expectancy or attention, and these dynamic patterns could allow the grouping and selection of distributed neuronal responses for further processing.

Consciousness and the binding problem.

It is proposed that phenomenal awareness, the ability to be aware of one's sensations and feelings, emerges from the capacity of evolved brains to analyze their own cognitive processes by iterating and reapplying on them-selves the very same cortical operations that they use for the interpretation of signals from the outer world. Search for the neuronal substrate of awareness therefore converges with the search for the cognitive mechanisms through which brains analyze their environment. The hypothesis is put forward that the mammalian brain generates continuously highly dynamic states that, when modulated by input signals, rapidly converge towards points of transient stability that correspond to the respective input constellation. It is proposed that these states are characterized by the dynamic binding of feature-specific cells into functionally coherent cell assemblies which as a whole represent the constellation of features defining a particular perceptual object. Arguments are presented that favor the notion that the cognitive operations supporting awareness consist of an iteration of such dynamic binding processes which then lead to the formation of higher-order assemblies that correspond to the contents of conscious awareness. Experimental data are reviewed relating to the questions of how assemblies are formed and which signatures define the relations among the responses of distributed neurons. It is argued that assemblies self-organize through reciprocal interactions of neurons coupled by reentrant loops and that the signature of relatedness consists of the transient synchronization of the discharges of the respective neurons. Evidence is presented that these synchronization phenomena depend on the same state variables as awareness: Both require for their manifestation activated brain states characterized by desynchronized EEGs. It is concluded that phenomenal awareness is amenable to neurobiological reductionism; but it is also proposed that self-consciousness requires a different explanatory approach because it emerges from the dialogue between different brains and hence has the quality of a cultural construct.

Sustained extrastriate cortical activation without visual awareness revealed by fMRI studies of hemianopic patients.

Patients with lesions in the primary visual cortex (V1) may show processing of visual stimuli presented in their field of cortical blindness even when they report being unaware of the stimuli. To elucidate the neuroanatomical basis of their residual visual functions, we used functional magnetic resonance imaging in two hemianopic patients, FS and GY. In the first experiment, a rotating spiral stimulus was used to assess the responsiveness of dorsal stream areas. Although no response was detectable within denervated or destroyed early visual cortex, motion-sensitive areas (hMT+/V5) ipsilateral to the lesion showed a strong sustained hemodynamic response. In GY, this activation was at least as strong as that of his contralesional hMT+/V5 to the stimulus in the normal hemifield. In the second experiment, coloured images of natural objects were used to assess the responsiveness of ventral stream areas. Again, no activity was detectable in ipsilesional early visual areas, but extrastriate areas in the lateral occipital cortex (hMT+/V5 and LO) and within the posterior fusiform gyrus (V4/V8) showed a robust sustained hemodynamic response. In both experiments, we observed that ipsilesional areas responded to stimuli presented in either hemifield, whereas the normal hemisphere responded preferentially to stimuli in the sighted hemifield. As only one subject occasionally noticed the onset of stimulation in the impaired field, the unexpectedly strong sustained activity in ipsilesional dorsal and ventral cortical areas appears to be insufficient to generate conscious vision.