Effects of Cortical Cooling on Sound Processing in Auditory Cortex and Thalamus of Awake Marmosets

The auditory thalamus is the central nexus of bottom-up connections from the inferior colliculus and top-down connections from auditory cortical areas. While considerable efforts have been made to investigate feedforward processing of sounds in the auditory thalamus (medial geniculate body, MGB) of non-human primates, little is known about the role of corticofugal feedback in the MGB of awake non-human primates. Therefore, we developed a small, repositionable cooling probe to manipulate corticofugal feedback and studied neural responses in both auditory cortex and thalamus to sounds under conditions of normal and reduced cortical temperature. Cooling-induced increases in the width of extracellularly recorded spikes in auditory cortex were observed over the distance of several hundred micrometers away from the cooling probe. Cortical neurons displayed reduction in both spontaneous and stimulus driven firing rates with decreased cortical temperatures. In thalamus, cortical cooling led to increased spontaneous firing and either increased or decreased stimulus driven activity. Furthermore, response tuning to modulation frequencies of temporally modulated sounds and spatial tuning to sound source location could be altered (increased or decreased) by cortical cooling. Specifically, best modulation frequencies of individual MGB neurons could shift either toward higher or lower frequencies based on the vector strength or the firing rate. The tuning of MGB neurons for spatial location could both sharpen or widen. Elevation preference could shift toward higher or lower elevations and azimuth tuning could move toward ipsilateral or contralateral locations. Such bidirectional changes were observed in many parameters which suggests that the auditory thalamus acts as a filter that could be adjusted according to behaviorally driven signals from auditory cortex. Future work will have to delineate the circuit elements responsible for the observed effects.

Kv4.2-Positive Domains on Dendrites in the Mouse Medial Geniculate Body Receive Ascending Excitatory and Inhibitory Inputs Preferentially From the Inferior Colliculus

The medial geniculate body (MGB) is the thalamic center of the auditory lemniscal pathway. The ventral division of MGB (MGV) receives excitatory and inhibitory inputs from the inferior colliculus (IC). MGV is involved in auditory attention by processing descending excitatory and inhibitory inputs from the auditory cortex (AC) and reticular thalamic nucleus (RTN), respectively. However, detailed mechanisms of the integration of different inputs in a single MGV neuron remain unclear. Kv4.2 is one of the isoforms of the Shal-related subfamily of potassium voltage-gated channels that are expressed in MGB. Since potassium channel is important for shaping synaptic current and spike waveforms, subcellular distribution of Kv4.2 is likely important for integration of various inputs. Here, we aimed to examine the detailed distribution of Kv4.2, in MGV neurons to understand its specific role in auditory attention. We found that Kv4.2 mRNA was expressed in most MGV neurons. At the protein level, Kv4.2-immunopositive patches were sparsely distributed in both the dendrites and the soma of neurons. The postsynaptic distribution of Kv4.2 protein was confirmed using electron microscopy (EM). The frequency of contact with Kv4.2-immunopositive puncta was higher in vesicular glutamate transporter 2 (VGluT2)-positive excitatory axon terminals, which are supposed to be extending from the IC, than in VGluT1-immunopositive terminals, which are expected to be originating from the AC. VGluT2-immunopositive terminals were significantly larger than VGluT1-immunopositive terminals. Furthermore, EM showed that the terminals forming asymmetric synapses with Kv4.2-immunopositive MGV dendritic domains were significantly larger than those forming synapses with Kv4.2-negative MGV dendritic domains. In inhibitory axons either from the IC or from the RTN, the frequency of terminals that were in contact with Kv4.2-positive puncta was higher in IC than in RTN. In summary, our study demonstrated that the Kv4.2-immunopositive domains of the MGV dendrites received excitatory and inhibitory ascending auditory inputs preferentially from the IC, and not from the RTN or cortex. Our findings imply that time course of synaptic current and spike waveforms elicited by IC inputs is modified in the Kv4.2 domains.

Information flow in the rat thalamo-cortical system: spontaneous vs. stimulus-evoked activities

The interaction between the thalamus and sensory cortex plays critical roles in sensory processing. Previous studies have revealed pathway-specific synaptic properties of thalamo-cortical connections. However, few studies to date have investigated how each pathway routes moment-to-moment information. Here, we simultaneously recorded neural activity in the auditory thalamus (or ventral division of the medial geniculate body; MGv) and primary auditory cortex (A1) with a laminar resolution in anesthetized rats. Transfer entropy (TE) was used as an information theoretic measure to operationalize “information flow”. Our analyses confirmed that communication between the thalamus and cortex was strengthened during presentation of auditory stimuli. In the resting state, thalamo-cortical communications almost disappeared, whereas intracortical communications were strengthened. The predominant source of information was the MGv at the onset of stimulus presentation and layer 5 during spontaneous activity. In turn, MGv was the major recipient of information from layer 6. TE suggested that a small but significant population of MGv-to-A1 pairs was “information-bearing,” whereas A1-to-MGv pairs typically exhibiting small effects played modulatory roles. These results highlight the capability of TE analyses to unlock novel avenues for bridging the gap between well-established anatomical knowledge of canonical microcircuits and physiological correlates via the concept of dynamic information flow.

Lemniscal Corticothalamic Feedback in Auditory Scene Analysis

Sound information is transmitted from the ear to central auditory stations of the brain via several nuclei. In addition to these ascending pathways there exist descending projections that can influence the information processing at each of these nuclei. A major descending pathway in the auditory system is the feedback projection from layer VI of the primary auditory cortex (A1) to the ventral division of medial geniculate body (MGBv) in the thalamus. The corticothalamic axons have small glutamatergic terminals that can modulate thalamic processing and thalamocortical information transmission. Corticothalamic neurons also provide input to GABAergic neurons of the thalamic reticular nucleus (TRN) that receives collaterals from the ascending thalamic axons. The balance of corticothalamic and TRN inputs has been shown to refine frequency tuning, firing patterns, and gating of MGBv neurons. Therefore, the thalamus is not merely a relay stage in the chain of auditory nuclei but does participate in complex aspects of sound processing that include top-down modulations. In this review, we aim (i) to examine how lemniscal corticothalamic feedback modulates responses in MGBv neurons, and (ii) to explore how the feedback contributes to auditory scene analysis, particularly on frequency and harmonic perception. Finally, we will discuss potential implications of the role of corticothalamic feedback in music and speech perception, where precise spectral and temporal processing is essential.

Corticofugal VIP Gabaergic Projection Neurons in the Mouse Auditory and Motor Cortex

Anatomical and physiological studies have described the cortex as a six-layer structure that receives, elaborates, and sends out information exclusively as excitatory output to cortical and subcortical regions. This concept has increasingly been challenged by several anatomical and functional studies that showed that direct inhibitory cortical outputs are also a common feature of the sensory and motor cortices. Similar to their excitatory counterparts, subsets of Somatostatin- and Parvalbumin-expressing neurons have been shown to innervate distal targets like the sensory and motor striatum and the contralateral cortex. However, no evidence of long-range VIP-expressing neurons, the third major class of GABAergic cortical inhibitory neurons, has been shown in such cortical regions. Here, using anatomical anterograde and retrograde viral tracing, we tested the hypothesis that VIP-expressing neurons of the mouse auditory and motor cortices can also send long-range projections to cortical and subcortical areas. We were able to demonstrate, for the first time, that VIP-expressing neurons of the auditory cortex can reach not only the contralateral auditory cortex and the ipsilateral striatum and amygdala, as shown for Somatostatin- and Parvalbumin-expressing long-range neurons, but also the medial geniculate body and both superior and inferior colliculus. We also demonstrate that VIP-expressing neurons of the motor cortex send long-range GABAergic projections to the dorsal striatum and contralateral cortex. Because of its presence in two such disparate cortical areas, this would suggest that the long-range VIP projection is likely a general feature of the cortex’s network.

Deep Brain Stimulation for Refractory Tinnitus: Pilot Study Protocol for a Randomized Double-Blinded Crossover Trial

Background: Chronic tinnitus can have an immense impact on quality of life. Despite recent treatment advances, many tinnitus patients remain refractory to them. Preclinical and clinical evidence suggest that deep brain stimulation (DBS) is as a promising treatment to suppress tinnitus. The thalamic medial geniculate body (MGB) takes a key position in the tinnitus network, shows pathophysiological hallmarks of tinnitus, and is readily accessible using stereotaxy. This study will evaluate the safety and therapeutic effects of DBS in the MGB in severe tinnitus sufferers.Methods: Bilateral DBS of the MGB will be applied in six patients with severe and refractory tinnitus. A double-blinded, randomized 2x2 crossover design (stimulation ON and OFF) will be applied, followed by a period of six months open label follow-up. The primary focus is to assess safety and feasibility (acceptability). Secondary outcomes assess a potential treatment effect and include tinnitus severity measured by the Tinnitus Functional Index (TFI), tinnitus loudness and distress, hearing, cognitive and psychological functions, quality of life, and neurophysiological characteristics. Discussion: Whilst carefully balancing risks and benefits and taking ethical considerations into account, this study explores the safety and feasibility of DBS in severe refractory tinnitus, by extensive assessment of clinical and neurophysiological outcome measures. Additionally, important insights in the underlying mechanism of tinnitus and hearing function might be revealed. Trial registration: ClinicalTrials.gov NCT03976908 (June 6, 2019)

Neuronal selectivity to complex vocalization features emerges in the superficial layers of primary auditory cortex

Early in auditory processing, neural responses faithfully reflect acoustic input. At higher stages of auditory processing, however, neurons become selective for particular call types, eventually leading to specialized regions of cortex that preferentially process calls at the highest auditory processing stages. We previously proposed that an intermediate step in how nonselective responses are transformed into call-selective responses is the detection of informative call features. But how neural selectivity for informative call features emerges from nonselective inputs, whether feature selectivity gradually emerges over the processing hierarchy, and how stimulus information is represented in nonselective and feature-selective populations remain open question. In this study, using unanesthetized guinea pigs (GPs), a highly vocal and social rodent, as an animal model, we characterized the neural representation of calls in 3 auditory processing stages—the thalamus (ventral medial geniculate body (vMGB)), and thalamorecipient (L4) and superficial layers (L2/3) of primary auditory cortex (A1). We found that neurons in vMGB and A1 L4 did not exhibit call-selective responses and responded throughout the call durations. However, A1 L2/3 neurons showed high call selectivity with about a third of neurons responding to only 1 or 2 call types. These A1 L2/3 neurons only responded to restricted portions of calls suggesting that they were highly selective for call features. Receptive fields of these A1 L2/3 neurons showed complex spectrotemporal structures that could underlie their high call feature selectivity. Information theoretic analysis revealed that in A1 L4, stimulus information was distributed over the population and was spread out over the call durations. In contrast, in A1 L2/3, individual neurons showed brief bursts of high stimulus-specific information and conveyed high levels of information per spike. These data demonstrate that a transformation in the neural representation of calls occurs between A1 L4 and A1 L2/3, leading to the emergence of a feature-based representation of calls in A1 L2/3. Our data thus suggest that observed cortical specializations for call processing emerge in A1 and set the stage for further mechanistic studies.

Corticothalamic Projections Deliver Enhanced-Responses to Medial Geniculate Body as a Function of the Temporal Reliability of the Stimulus

Aging and challenging signal-in-noise conditions are known to engage use of cortical resources to help maintain speech understanding. Extensive corticothalamic projections are thought to provide attentional, mnemonic and cognitive-related inputs in support of sensory inferior colliculus (IC) inputs to the medial geniculate body (MGB). Here we show that a decrease in modulation depth, a temporally less distinct periodic acoustic signal, leads to a jittered ascending temporal code, changing MGB unit responses from adapting responses to responses showing repetition-enhancement, posited to aid identification of important communication and environmental sounds. Young-adult male Fischer Brown Norway rats, injected with the inhibitory opsin archaerhodopsin T (ArchT) into the primary auditory cortex (A1), were subsequently studied using optetrodes to record single-units in MGB. Decreasing the modulation depth of acoustic stimuli significantly increased repetition-enhancement. Repetition-enhancement was blocked by optical inactivation of corticothalamic terminals in MGB. These data support a role for corticothalamic projections in repetition-enhancement, implying that predictive anticipation could be used to improve neural representation of weakly modulated sounds.

Auditory thalamus dysfunction and pathophysiology in tinnitus: a predictive network hypothesis

Tinnitus is the perception of a ‘ringing’ sound without an acoustic source. It is generally accepted that tinnitus develops after peripheral hearing loss and is associated with altered auditory processing. The thalamus is a crucial relay in the underlying pathways that actively shapes processing of auditory signals before the respective information reaches the cerebral cortex. Here, we review animal and human evidence to define thalamic function in tinnitus. Overall increased spontaneous firing patterns and altered coherence between the thalamic medial geniculate body (MGB) and auditory cortices is observed in animal models of tinnitus. It is likely that the functional connectivity between the MGB and primary and secondary auditory cortices is reduced in humans. Conversely, there are indications for increased connectivity between the MGB and several areas in the cingulate cortex and posterior cerebellar regions, as well as variability in connectivity between the MGB and frontal areas regarding laterality and orientation in the inferior, medial and superior frontal gyrus. We suggest that these changes affect adaptive sensory gating of temporal and spectral sound features along the auditory pathway, reflecting dysfunction in an extensive thalamo-cortical network implicated in predictive temporal adaptation to the auditory environment. Modulation of temporal characteristics of input signals might hence factor into a thalamo-cortical dysrhythmia profile of tinnitus, but could ultimately also establish new directions for treatment options for persons with tinnitus.