Acoustic factors govern developmental sharpening of spatial tuning in the auditory cortex

Auditory localization relies on the detection and interpretation of acoustic cues that change in value as the head and external ears grow. Here we show that the maturation of these structures is an important determinant for the development of spatial selectivity in the ferret auditory cortex. Spatial response fields (SRFs) of high-frequency cortical neurons recorded at postnatal days (P) 33-39 were broader, and transmitted less information about stimulus direction, than in older ferrets. They also exhibited slightly broader frequency tuning than neurons recorded in adult animals. However, when infant neurons were stimulated through virtual ears of adults, SRFs sharpened significantly and the amount of transmitted information increased. This improvement was predicted by a model that generates SRF shape from the localization cue values and the neurons' binaural spectrotemporal response properties. The maturation of spatial response characteristics in auditory cortex therefore seems to be limited by peripheral rather than by central factors.     

Binaural sensitivity changes between cortical on and off responses

Neurons exhibiting on and off responses with different frequency tuning have previously been described in the primary auditory cortex (A1) of anesthetized and awake animals, but it is unknown whether other tuning properties, including sensitivity to binaural localization cues, also differ between on and off responses. We measured the sensitivity of A1 neurons in anesthetized ferrets to 1) interaural level differences (ILDs), using unmodulated broadband noise with varying ILDs and average binaural levels, and 2) interaural time delays (ITDs), using sinusoidally amplitude-modulated broadband noise with varying envelope ITDs. We also assessed fine-structure ITD sensitivity and frequency tuning, using pure-tone stimuli. Neurons most commonly responded to stimulus onset only, but purely off responses and on-off responses were also recorded. Of the units exhibiting significant binaural sensitivity nearly one-quarter showed binaural sensitivity in both on and off responses, but in almost all (～97%) of these units the binaural tuning of the on responses differed significantly from that seen in the off responses. Moreover, averaged, normalized ILD and ITD tuning curves calculated from all units showing significant sensitivity to binaural cues indicated that on and off responses displayed different sensitivity patterns across the population. A principal component analysis of ITD response functions suggested a continuous cortical distribution of binaural sensitivity, rather than discrete response classes. Rather than reflecting a release from inhibition without any functional significance, we propose that binaural off responses may be important to cortical encoding of sound-source location.     

Shifting and scaling adaptation to dynamic stimuli in somatosensory cortex

Recent reports have shown that responses of midbrain neurons in the guinea pig rapidly shift the dynamic range of their responses to track changes in the statistics of ongoing sound-level distributions. This results in an increased coding accuracy for the most commonly occurring stimulus intensities. To investigate whether this type of adaptation might also be found in other sensory modalities, we characterized the intensity-response functions of neurons in rat primary somatosensory cortex (S1) to continuous sinusoidal vibration of the whiskers with amplitudes that were changed every 40 ms. Vibration amplitudes were selected randomly such that there was an 80% chance for the amplitude to be drawn from a relatively narrow 'high-probability region' (HPR). Stimulus mean and variance were then manipulated by shifting or widening the HPR. We found that rat S1 neurons adapt to shifts of the HPR mainly by shifting their thresholds, and to changes in HPR width by changing the slope of their rate-level curves. Using realistic single-neuron models, we go on to show that after-hyperpolarizing currents, such as those carried by K(Ca)(2+) channels, may be responsible for the threshold shifts, but not the slope changes.     

Linking cortical spike pattern codes to auditory perception

Abstract Neurometric analysis has proven to be a powerful tool for studying links between neural activity and perception, especially in visual and somatosensory cortices, but conventional neurometrics are based on a simplistic rate-coding hypothesis that is clearly at odds with the rich and complex temporal spiking patterns evoked by many natural stimuli. In this study, we investigated the possible relationships between temporal spike pattern codes in the primary auditory cortex (A1) and the perceptual detection of subtle changes in the temporal structure of a natural sound. Using a two-alternative forced-choice oddity task, we measured the ability of human listeners to detect local time reversals in a marmoset twitter call. We also recorded responses of neurons in A1 of anesthetized and awake ferrets to these stimuli, and analyzed these responses using a novel neurometric approach that is sensitive to temporal discharge patterns. We found that although spike count-based neurometrics were inadequate to account for behavioral performance on this auditory task, neurometrics based on the temporal discharge patterns of populations of A1 units closely matched the psychometric performance curve, but only if the spiking patterns were resolved at temporal resolutions of 20 msec or better. These results demonstrate that neurometric discrimination curves can be calculated for temporal spiking patterns, and they suggest that such an extension of previous spike count-based approaches is likely to be essential for understanding the neural correlates of the perception of stimuli with a complex temporal structure.     

Tell me something interesting: context dependent adaptation in somatosensory cortex

It is widely accepted that through a process of adaptation cells adjust their sensitivity in accordance with prevailing stimulus conditions. However, in two recent studies exploring adaptation in the rodent inferior colliculus and somatosensory cortex, neurons did not adapt towards global mean, but rather became most sensitive to inputs that were located towards the edge of the stimulus distribution with greater intensity than the mean. We re-examined electrophysiological data from the somatosensory study with the purpose of exploring the underlying encoding strategies. We found that neural gain tended to decrease as stimulus variance increased. Following adaptation to changes in global mean, neuronal output was scaled such that the relationship between firing rate and local, rather than global, differences in stimulus intensity was maintained. The majority of cells responded to large, positive deviations in stimulus amplitude; with a small number responding to both positive and negative changes in stimulus intensity. Adaptation to global mean was replicated in a model neuron by incorporating both spike-rate adaptation and tonic-inhibition, which increased in proportion to stimulus mean. Adaptation to stimulus variance was replicated by approximating the output of a population of neurons adapted to global mean and using it to drive a layer of recurrently connected depressing synapses. Within the barrel cortex, adaptation ensures that neurons are able to encode both overall levels of variance and large deviations in the input. This is achieved through a combination of gain modulation and a shift in sensitivity to intensity levels that are greater than the mean.     

Clinical benefit of left atrial appendage closure in octogenarians

OBJECTIVESWhether left atrial appendage closure (LAAC) in octogenarians yield similar net clinical benefit compared to younger patients, was the purpose of the present study.METHODSTwo real-world LAAC registries, enrolling 744 consecutive Amplatzer and Watchman patients from 2009 to 2018, were retrospectively analyzed.RESULTSAll events are reported per 100 patient-years. Two hundred and sixty one octogenarians and 483 non-octogenarians with a mean follow-up of 1.7 ± 1.3 and 2.3 ± 1.6 years, and a total of 1,502 patient-years were included. Octogenarians had a higher risk for stroke (CHA₂DS₂-VASc score: 5.2 ± 1.2 vs. 4.3 ± 1.7, P < 0.0001) and bleeding (HAS-BLED score: 3.3 ± 0.8 vs. 3.1 ± 1.1, P = 0.001). The combined safety endpoint of major periprocedural complications and major bleeding events at follow-up was comparable (30/446, 6.7% vs. 47/1056, 4.4%; hazard ratio [HR] = 1.2; 95% confidence interval [CI]: 0.73−1.98;P = 0.48) between the groups. The efficacy endpoint of all-cause stroke, systemic embolism, and cardiovascular/unexplained death occurred more often in octogenarians (61/446, 13.7% vs. 80/1056, 7.6%; HR = 7.0; 95% CI: 4.53−10.93;P < 0.0001). Overall, octogenarians had a lower net clinical benefit, i.e., the composite of all above mentioned hazards, from LAAC compared to younger patients (82/446, 18.4% vs. 116/1056, 11.0%; HR = 4.6; 95% CI: 3.11−7.0;P < 0.0001). Compared to the anticipated stroke rate, the observed rate decreased by 41% in octogenarians and 53% in non-octogenarians. The observed bleeding rate was reduced by 10% octogenarians and 41% non-octogenarians. CONCLUSIONSLAAC can be performed with similar safety in octogenarians as compared to younger patients. On the long-term, it both reduces stroke and bleeding events, although to a lesser extent than in non-octogenarians.

As the most frequent arrhythmia, atrial fibrillation (AF) is associated with an increased risk of cognitive decline, stroke, disability, and mortality. The prevalence of AF is 2% in the general population and roses steadily with age, 3.7%−4.2% of subjects are aged above 60 years and up to 17% are octogenarians (age ≥ 80 years).^[1] Stroke risk from AF increases exponentially with age and is estimated at 23.9% per year in patients aged 80 years and older.^[2] Additionally, patients ≥ 80 years with AF, who are treated with oral anticoagulation (OAC), have a higher incidence of hemorrhagic events than younger patients.^[3] Therefore, octogenarians with AF are at highest risk for both thromboembolic and bleeding events. OAC is the standard of care for stroke risk. However, clinical evidence shows underuse of OAC in the elderly, who would have the highest benefit regarding ischemic stroke risk. This is mainly due to concerns about bleeding or prior bleedings. Factors of comorbidity, like impaired cognition, nonadherence, history of falls or bleedings, renal dysfunction, as well as concomitant drugs are reasons for leaving a substantial fraction of patients without stroke protection by OAC.^[4] Left atrial appendage closure (LAAC) is recommended as an alternative strategy for stroke prevention in AF patients who are not suitable for long-term treatment with OAC.^[5,6] Therefore, LAAC might be an attractive option for elderly AF patients. Several studies reported similar feasibility and safety of LAAC in subjects aged > 75 years compared to younger patients. ^[7–11] Furthermore, those studies showed favorable early clinical outcomes with regard to stroke and bleeding protection. Whether elderly patients have persistent long-term effects of LAAC has not been studied yet. Therefore, the subject of the present study was to compare the clinical benefit of LAAC in octogenarians with non-octogenarians based on the results of two real-world registries.