Electrophysiology publications

Synchronized states are marked by large-amplitude low-frequency oscillations in the cortex. These states can be seen during quiet waking or slow-wave sleep. Within synchronized states, previous studies have noted a plethora of different types of activity, including delta oscillations (0.5-4 Hz) and slow oscillations (<1 Hz) in the neocortex and large- and small- irregular activity in the hippocampus. However, it is not still fully characterized how neural populations contribute to the synchronized state. Here we apply independent component analysis to parse which populations are involved in different kinds of neocortical activity, and find two populations that alternate throughout synchronized states. One population broadly affects neocortical deep layers, and is associated with larger amplitude slower neocortical oscillations. The other population exhibits theta-frequency oscillations that are not easily observed in raw field potential recordings. These theta oscillations apparently come from below the neocortex, suggesting hippocampal origin, and are associated with smaller amplitude faster neocortical oscillations. Relative involvement of these two alternating populations may indicate different modes of operation within synchronized states.

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

The accuracy of the neural code depends on the relative embedding of signal and noise in the activity of neural populations. Despite a wealth of theoretical work on population codes, there are few empirical characterizations of the high-dimensional signal and noise subspaces. We studied the geometry of population codes in the rat auditory cortex across brain states along the activation-inactivation continuum, using sounds varying in difference and mean level across the ears. As the cortex becomes more activated, single-hemisphere populations go from preferring contralateral loud sounds to a symmetric preference across lateralizations and intensities, gain-modulation effectively disappears, and the signal and noise subspaces become approximately orthogonal to each other and to the direction corresponding to global activity modulations. Level-invariant decoding of sound lateralization also becomes possible in the active state. Our results provide an empirical foundation for the geometry and state-dependence of cortical population codes.

What determines how we move in the world? Motor neuroscience often focusses either on intrinsic rhythmical properties of motor circuits or extrinsic sensorimotor feedback loops. Here we show that the interplay of both intrinsic and extrinsic dynamics is required to explain the intermittency observed in continuous tracking movements. Using spatiotemporal perturbations in humans, we demonstrate that apparently discrete submovements made 2–3 times per second reflect constructive interference between motor errors and continuous feedback corrections that are filtered by intrinsic circuitry in the motor system. Local field potentials in monkey motor cortex revealed characteristic signatures of a Kalman filter, giving rise to both low-frequency cortical cycles during movement, and delta oscillations during sleep. We interpret these results within the framework of optimal feedback control, and suggest that the intrinsic rhythmicity of motor cortical networks reflects an internal model of external dynamics, which is used for state estimation during feedback-guided movement. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Intensity and frequency are the two main properties of sound. The non-monotonic neurons in the auditory system are thought to represent sound intensity. The central nucleus of the inferior colliculus (ICC), as an important information integration nucleus of the auditory system, is also involved in the processing of intensity encoding. Although previous researchers have hinted at the importance of inhibitory effects on the formation of non-monotonic neurons, the specific underlying synaptic mechanisms in the ICC are still unclear. Therefore, we applied the in vivo whole-cell voltage-clamp technique to record the excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) in the ICC neurons, and compared the effects of excitation and inhibition on the membrane potential outputs. We found that non-monotonic neuron responses could not only be inherited from the lower nucleus but also be created in the ICC. By integrating with a relatively weak IPSC, approximately 35% of the monotonic excitatory inputs remained in the ICC. In the remaining cases, monotonic excitatory inputs were reshaped into non-monotonic outputs by the dominating inhibition at high intensity, which also enhanced the non-monotonic nature of the non-monotonic excitatory inputs.

Neural computations occurring simultaneously in multiple cerebral cortical regions are critical for mediating behaviors. Progress has been made in understanding how neural activity in specific cortical regions contributes to behavior. However, there is a lack of tools that allow simultaneous monitoring and perturbing neural activity from multiple cortical regions. We engineered ‘See-Shells’—digitally designed, morphologically realistic, transparent polymer skulls that allow long-term (>300 days) optical access to 45 mm 2 of the dorsal cerebral cortex in the mouse. We demonstrate the ability to perform mesoscopic imaging, as well as cellular and subcellular resolution two-photon imaging of neural structures up to 600 µm deep. See-Shells allow calcium imaging from multiple, non-contiguous regions across the cortex. Perforated See-Shells enable introducing penetrating neural probes to perturb or record neural activity simultaneously with whole cortex imaging. See-Shells are constructed using common desktop fabrication tools, providing a powerful tool for investigating brain structure and function.

Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded in vivo in mice lacking the gene (Fmr1-/y ) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in Fmr1-/y animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K+ currents that activate at positive potentials ("high-threshold" K+ currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in Fmr1-/y mice, while K+ currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 [((4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile], a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K+ current and increased the low-threshold K+ currents in neurons from Fmr1-/y animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and, in vivo, restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS.SIGNIFICANCE STATEMENT mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses in vivo, suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.

Salience is a broad and widely used concept in neuroscience whose neuronal correlates, however, remain elusive. In behavioral conditioning, salience is used to explain various effects, such as stimulus overshadowing, and refers to how fast and strongly a stimulus can be associated with a conditioned event. Here, we identify sounds of equal intensity and perceptual detectability, which due to their spectro-temporal content recruit different levels of population activity in mouse auditory cortex. When using these sounds as cues in a Go/NoGo discrimination task, the degree of cortical recruitment matches the salience parameter of a reinforcement learning model used to analyze learning speed. We test an essential prediction of this model by training mice to discriminate light-sculpted optogenetic activity patterns in auditory cortex, and verify that cortical recruitment causally determines association or overshadowing of the stimulus components. This demonstrates that cortical recruitment underlies major aspects of stimulus salience during reinforcement learning.

Cisplatin-induced ototoxicity results in significant, permanent hearing loss in pediatric and adult cancer survivors. Elucidating the mechanisms underlying cisplatin-induced hearing loss as well as the development of therapies to reduce and/or reverse cisplatin ototoxicity have been impeded by suboptimal animal models. Clinically, cisplatin is most commonly administered in multi-dose, multi-cycle protocols. However, many animal studies are conducted using single injections of high-dose cisplatin, which is not reflective of clinical cisplatin administration protocols. Significant limitations of both high-dose, single-injection protocols and previous multi-dose protocols in rodent models include high mortality rates and relatively small changes in hearing sensitivity. These limitations restrict assessment of both long-term changes in hearing sensitivity and effects of potential protective therapies. Here, we present a detailed method for an optimized mouse model of cisplatin ototoxicity that utilizes a multi-cycle administration protocol that better approximates the type and degree of hearing loss observed clinically. This protocol results in significant hearing loss with very low mortality. This mouse model of cisplatin ototoxicity provides a platform for examining mechanisms of cisplatin-induced hearing loss as well as developing therapies to protect the hearing of cancer patients receiving cisplatin therapy.

An inductively-powered wireless integrated neural recording and stimulation (WINeRS-8) system-on-a-chip (SoC) that is compatible with the EnerCage-HC2 for wireless/battery-less operation has been presented for neuroscience experiments on freely behaving animals. WINeRS-8 includes a 32-ch recording analog front end, a 4-ch current-controlled stimulator, and a 434 MHz on - off keying data link to an external software- defined radio wideband receiver (Rx). The headstage also has a bluetooth low energy link for controlling the SoC. WINeRS-8/EnerCage-HC2 systems form a bidirectional wireless and battery-less neural interface within a standard homecage, which can support longitudinal experiments in an enriched environment. Both systems were verified in vivo on rat animal model, and the recorded signals were compared with hardwired and battery-powered recording results. Realtime stimulation and recording verified the system's potential for bidirectional neural interfacing within the homecage, while continuously delivering 35 mW to the hybrid WINeRS-8 headstage over an unlimited period.

The medial septum implements cortical theta oscillations, a 5-12 Hz rhythm associated with locomotion and paradoxical sleep reflecting synchronization of neuronal assemblies such as place cell sequence coding. Highly rhythmic burst-firing parvalbumin-positive GABAergic medial septal neurons are strongly coupled to theta oscillations and target cortical GABAergic interneurons, contributing to coordination within one or several cortical regions. However, a large population of medial septal neurons of unidentified neurotransmitter phenotype and with unknown axonal target areas fire with a low degree of rhythmicity. We investigated whether low-rhythmic-firing neurons (LRNs) innervated similar or different cortical regions to high-rhythmic-firing neurons (HRNs) and assessed their temporal dynamics in awake male mice. The majority of LRNs were GABAergic and parvalbumin-immunonegative, some expressing calbindin; they innervated interneurons mostly in the dentate gyrus (DG) and CA3. Individual LRNs showed several distinct firing patterns during immobility and locomotion, forming a parallel inhibitory stream for the modulation of cortical interneurons. Despite their fluctuating firing rates, the preferred firing phase of LRNs during theta oscillations matched the highest firing probability phase of principal cells in the DG and CA3. In addition, as a population, LRNs were markedly suppressed during hippocampal sharp-wave ripples, had a low burst incidence, and several of them did not fire on all theta cycles. Therefore, CA3 receives GABAergic input from both HRNs and LRNs, but the DG receives mainly LRN input. We propose that distinct GABAergic LRNs contribute to changing the excitability of the DG and CA3 during memory discrimination via transient disinhibition of principal cells.SIGNIFICANCE STATEMENT For the encoding and recall of episodic memories, nerve cells in the cerebral cortex are activated in precisely timed sequences. Rhythmicity facilitates the coordination of neuronal activity and these rhythms are detected as oscillations of different frequencies such as 5-12 Hz theta oscillations. Degradation of these rhythms, such as through neurodegeneration, causes memory deficits. The medial septum, a part of the basal forebrain that innervates the hippocampal formation, contains high- and low-rhythmic-firing neurons (HRNs and LRNs, respectively), which may contribute differentially to cortical neuronal coordination. We discovered that GABAergic LRNs preferentially innervate the dentate gyrus and the CA3 area of the hippocampus, regions important for episodic memory. These neurons act in parallel with the HRNs mostly via transient inhibition of inhibitory neurons.

Sound information is transduced into graded receptor potential by cochlear hair cells and encoded as discrete action potentials of auditory nerve fibers. In the cochlear nucleus, auditory nerve fibers convey this information through morphologically distinct synaptic terminals onto bushy cells (BCs) and stellate cells (SCs) for processing of different sound features. With expanding use of transgenic mouse models, it is increasingly important to understand the in vivo functional development of these neurons in mice. We characterized the maturation of spontaneous and acoustically evoked activity in BCs and SCs by acquiring single-unit juxtacellular recordings between hearing onset (P12) and young adulthood (P30) of anesthetized CBA/J mice. In both cell types, hearing sensitivity and characteristic frequency (CF) range are mostly adult-like by P14, consistent with rapid maturation of the auditory periphery. In BCs, however, some physiological features like maximal firing rate, dynamic range, temporal response properties, recovery from post-stimulus depression, first spike latency (FSL) and encoding of sinusoid amplitude modulation undergo further maturation up to P18. In SCs, the development of excitatory responses is even more prolonged, indicated by a gradual increase in spontaneous and maximum firing rates up to P30. In the same cell type, broadly tuned acoustically evoked inhibition is immediately effective at hearing onset, covering the low- and high-frequency flanks of the excitatory response area. Together, these data suggest that maturation of auditory processing in the parallel ascending BC and SC streams engages distinct mechanisms at the first central synapses that may differently depend on the early auditory experience.

Detection of interaural time differences (ITDs) is crucial for sound localization in most vertebrates. The current view is that optimal computational strategies of ITD detection depend mainly on head size and available frequencies, although evolutionary history should also be taken into consideration. In archosaurs, which include birds and crocodiles, the brainstem nucleus laminaris (NL) developed into the critical structure for ITD detection. In birds, ITDs are mapped in an orderly array or place code, whereas in the mammalian medial superior olive, the analog of NL, maps are not found. As yet, in crocodilians, topographical representations have not been identified. However, nontopographic representations of ITD cannot be excluded due to different anatomical and ethological features of birds and crocodiles. Therefore, we measured ITD-dependent responses in the NL of anesthetized American alligators of either sex and identified the location of the recording sites by lesions made after recording. The measured extracellular field potentials, or neurophonics, were strongly ITD tuned, and their preferred ITDs correlated with the position in NL. As in birds, delay lines, which compensate for external time differences, formed maps of ITD. The broad distributions of best ITDs within narrow frequency bands were not consistent with an optimal coding model. We conclude that the available acoustic cues and the architecture of the acoustic system in early archosaurs led to a stable and similar organization in today's birds and crocodiles, although physical features, such as internally coupled ears, head size, or shape, and audible frequency range, vary among the two groups. SIGNIFICANCE STATEMENT Interaural time difference (ITD) is an important cue for sound localization, and the optimal strategies for encoding ITD in neuronal populations are the subject of ongoing debate. We show that alligators form maps of ITD very similar to birds, suggesting that their common archosaur ancestor reached a stable coding solution different from mammals. Mammals and diapsids evolved tympanic hearing independently, and local optima can be reached in evolution that are not considered by global optimal coding models. Thus, the presence of ITD maps in the brainstem may reflect a local optimum in evolutionary development. Our results underline the importance of comparative animal studies and show that optimal models must be viewed in the light of evolutionary processes.

Pitch perception is critical for recognizing speech, music and animal vocalizations, but its neurobiological basis remains unsettled, in part because of divergent results across species. We investigated whether species-specific differences exist in the cues used to perceive pitch and whether these can be accounted for by differences in the auditory periphery. Ferrets accurately generalized pitch discriminations to untrained stimuli whenever temporal envelope cues were robust in the probe sounds, but not when resolved harmonics were the main available cue. By contrast, human listeners exhibited the opposite pattern of results on an analogous task, consistent with previous studies. Simulated cochlear responses in the two species suggest that differences in the relative salience of the two pitch cues can be attributed to differences in cochlear filter bandwidths. The results support the view that cross-species variation in pitch perception reflects the constraints of estimating a sound’s fundamental frequency given species-specific cochlear tuning.

The deep cerebellar nuclei (DCN) have been suggested to play a critical role in sensorimotor learning and some forms of long-term synaptic plasticity observed in vitro have been proposed as a possible substrate. However, till now it was not clear whether and how DCN neuron responses manifest long-lasting changes in vivo. Here, we have characterized DCN unit responses to tactile stimulation of the facial area in anesthetized mice and evaluated the changes induced by theta-sensory stimulation (TSS), a 4 Hz stimulation pattern that is known to induce plasticity in the cerebellar cortex in vivo. DCN units responded to tactile stimulation generating bursts and pauses, which reflected combinations of excitatory inputs most likely relayed by mossy fiber collaterals, inhibitory inputs relayed by Purkinje cells, and intrinsic rebound firing. Interestingly, initial bursts and pauses were often followed by stimulus-induced oscillations in the peri-stimulus time histograms (PSTH). TSS induced long-lasting changes in DCN unit responses. Spike-related potentiation and suppression (SR-P and SR-S), either in units initiating the response with bursts or pauses, were correlated with stimulus-induced oscillations. Fitting with resonant functions suggested the existence of peaks in the theta-band (burst SR-P at 9 Hz, pause SR-S at 5 Hz). Optogenetic stimulation of the cerebellar cortex altered stimulus-induced oscillations suggesting that Purkinje cells play a critical role in the circuits controlling DCN oscillations and plasticity. This observation complements those reported before on the granular and molecular layers supporting the generation of multiple distributed plasticities in the cerebellum following naturally patterned sensory entrainment. The unique dependency of DCN plasticity on circuit oscillations discloses a potential relationship between cerebellar learning and activity patterns generated in the cerebellar network.

The inferior colliculus (IC) is known as a neuronal structure involved in the integration of acoustic information in the ascending auditory pathway. However, the processing of paired acoustic stimuli containing different sound types, especially when they are applied closely, in the IC remains poorly studied. We here firstly investigated the IC neuronal response to the paired stimuli comprising click and pure tone with different inter-stimulus (click-tone) intervals using in vivo loose-patch recordings in anesthetized BALB/c mice. It was found that the total acoustic evoked spike counts decreased under certain click-tone interval conditions on some neurons with or without click-induced supra-threshold responses. Application of click could enhance the minimum threshold of the neurons responding to the tone in a pair without changing other characteristics of the neuronal tone receptive fields. We further studied the paired acoustic stimuli evoked excitatory/inhibitory inputs, IC neurons received, by holding the membrane potential at -70/0 mV using in vivo whole-cell voltage-clamp techniques. The curvature and peak amplitude of the excitatory/inhibitory post-synaptic current (EPSC/IPSC) could be almost unchanged under different inter-stimulus interval conditions. Instead of showing the summation of synaptic inputs, most recorded neurons only had the EPSC/IPSC with the amplitude similar as the bigger one evoked by click or tone in a pair when the inter-stimulus interval was small. We speculated that the IC could inherit the paired click-tone information which had been integrated before reaching it.

Transmitter release at auditory inner hair cell (IHC) ribbon synapses involves exocytosis of glutamatergic vesicles during voltage activation of L-type Cav1.3 calcium channels. At these synapses, the fast and indefatigable release of synaptic vesicles by IHCs is controlled by otoferlin, a six-C2-domain (C2-ABCDEF) protein that functions as a high-affinity Ca2+ sensor. The molecular events by which each otoferlin C2 domain contributes to the regulation of the synaptic vesicle cycle in IHCs are still incompletely understood. Here, we investigate their role using a cochlear viral cDNA transfer approach in vivo, where IHCs of mouse lacking otoferlin (Otof-/- mice of both sexes) were virally transduced with cDNAs of various mini-otoferlins. Using patch-clamp recordings and membrane capacitance measurements, we show that the viral transfer of mini-otoferlin containing C2-ACEF, C2-EF, or C2-DEF partially restores the fast exocytotic component in Otof-/- mouse IHCs. The restoration was much less efficient with C2-ACDF, underlining the importance of the C2-EF domain. None of the mini-otoferlins tested restored the sustained component of vesicle release, explaining the absence of hearing recovery. The restoration of the fast exocytotic component in the transduced Otof-/- IHCs was also associated with a recovery of Ca2+ currents with normal amplitude and fast time inactivation, confirming that the C-terminal C2 domains of otoferlin are essential for normal gating of Cav1.3 channels. Finally, the reintroduction of the mini-otoferlins C2-EF, C2-DEF, or C2-ACEF allowed us to uncover and characterize for the first time a dynamin-dependent ultrafast endocytosis in IHCs.SIGNIFICANCE STATEMENT Otoferlin, a large six-C2-domain protein, is essential for synaptic vesicle exocytosis at auditory hair cell ribbon synapses. Here, we show that the viral expression of truncated forms of otoferlin (C2-EF, C2-DEF, and C2-ACEF) can partially rescue the fast and transient release component of exocytosis in mouse hair cells lacking otoferlin, yet cannot sustain exocytosis after long repeated stimulation. Remarkably, these hair cells also display a dynamin-dependent ultrafast endocytosis. Overall, our study uncovers the pleiotropic role of otoferlin in the hair cell synaptic vesicle cycle, notably in triggering both ultrafast exocytosis and endocytosis and recruiting synaptic vesicles to the active zone.

Direct cortical stimulation (DCS) of primary somatosensory cortex (S1) could help restore sensation and provide task-relevant feedback in a neuroprosthesis. However, the psychophysics of S1 DCS is poorly studied, including any comparison to cutaneous haptic stimulation. We compare the response times to DCS of human hand somatosensory cortex through electrocorticographic grids with response times to haptic stimuli delivered to the hand in four subjects. We found that subjects respond significantly slower to S1 DCS than to natural, haptic stimuli for a range of DCS train durations. Median response times for haptic stimulation varied from 198 ms to 313 ms, while median responses to reliably perceived DCS ranged from 254 ms for one subject, all the way to 528 ms for another. We discern no significant impact of learning or habituation through the analysis of blocked trials, and find no significant impact of cortical stimulation train duration on response times. Our results provide a realistic set of expectations for latencies with somatosensory DCS feedback for future neuroprosthetic applications and motivate the study of neural mechanisms underlying human perception of somatosensation via DCS.

Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry, electrophysiology, immunohistochemistry, and neural manipulation strategies, we determined the population dynamics of four molecularly delineated PVH subsets implicated in feeding behavior: glucagon-like peptide 1 receptor (PVHGlp1r), melanocortin-4 receptor (PVHMc4r), oxytocin (PVHOxt), and corticotropin-releasing hormone (PVHCrh). We identified both calorie- and state-dependent sustained activity increases and decreases in PVHGlp1r and PVHCrh populations, respectively, while observing transient bulk changes of PVHMc4r, but no response in PVHOxt, neurons to food. Furthermore, we highlight the role of PVHGlp1r neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVHGlp1r and PVHMc4r, but not PVHOxt or PVHCrh neurons, in body weight maintenance.

Sensory perception arises from the integration of externally and internally driven representations of the world. Disrupted balance of these representations can lead to perceptual deficits and hallucinations. The serotonin-2A receptor (5-HT2AR) is associated with such perceptual alterations, both in its role in schizophrenia and in the action of hallucinogenic drugs. Despite this powerful influence on perception, relatively little is known about how serotonergic hallucinogens influence sensory processing in the neocortex. Using widefield and two-photon calcium imaging and single-unit electrophysiology in awake mice, we find that administration of the hallucinogenic selective 5-HT2AR agonist DOI (2,5-dimethoxy-4-iodoamphetamine) leads to a net reduction in visual response amplitude and surround suppression in primary visual cortex, as well as disrupted temporal dynamics. However, basic retinotopic organization, tuning properties, and receptive field structure remain intact. Our results provide support for models of hallucinations in which reduced bottom-up sensory drive is a key factor leading to altered perception.