Cross-modal interactions of auditory and somatic inputs in the brainstem and midbrain and their imbalance in tinnitus and deafness

Abstract

Purpose: This review outlines the anatomical and functional bases of somatosensory influences on auditory processing in the normal brainstem and midbrain. It then explores how interactions between the auditory and somatosensory system are modified through deafness, and their impact on tinnitus is discussed.

Method: Literature review, tract tracing, immunohistochemistry, and in vivo electrophysiological recordings were used.

Results: Somatosensory input originates in the dorsal root ganglia and trigeminal ganglia, and is transmitted directly and indirectly through 2nd-order nuclei to the ventral cochlear nucleus, dorsal cochlear nucleus (DCN), and inferior colliculus. The glutamatergic somatosensory afferents can be segregated from auditory nerve inputs by the type of vesicular glutamate transporters present in their terminals. Electrical stimulation of the somatosensory input results in a complex combination of excitation and inhibition, and alters the rate and timing of responses to acoustic stimulation. Deafness increases the spontaneous rates of those neurons that receive excitatory somatosensory input and results in a greater sensitivity of DCN neurons to trigeminal stimulation.

Conclusions: Auditory-somatosensory bimodal integration is already present in 1st-order auditory nuclei. The balance of excitation and inhibition elicited by somatosensory input is altered following deafness. The increase in somatosensory influence on auditory neurons when their auditory input is diminished could be due to cross-modal reinnervation or increased synaptic strength, and may contribute to mechanisms underlying somatic tinnitus.

Figure 1

Schematic overview of the pathways connecting the somatosensory and auditory system. Arrows connect the origins and target of inputs. Ascending inputs arise in the spiral ganglion (pink, SG), vestibular ganglion (yellow, VG), dorsal root ganglia (red, DRG), trigeminal ganglion (dark blue, TG), lateral reticlar formation (green, RVL, LPGi) and pontine nuclei (light blue). Projections ascending from the brainstem trigeminal complex are marked purple and from the dorsal column are marked orange. Dashed lines mark the contralateral projectons, crossing midline (dotted line). ➀: Dorsal column-medial lemniscal system; ➁: Spinothalamic pathway of the anterolateral system. The brainstem trigeminal sensory omplex is comprised of three nuclei: ➂: principle nucleus; ➃: mesecephalic nucleus, ➄: spinal trigeminal nucleus (SP5). The SP5 consists of three parts: pars oralis (SP5O), pars interpolaris (SP5I), pars caudalis (SP5C), SP5C has three subnuclei: subnucleus magnocellularis, subnucleus gelatinosus, subnucleus marginalis. ➅: three braches of the trigeminal nerve:1-ophthalmic branch: innervates forehead, upper eyelid, extraocular muscles; 2-maxillar branch: innervates upper lip, lower eyelid, upper jaw, roof of the mouth; 3-mandibular branch: innervates lower lip, mucous membranes of the lower jaw, floor of the mouth, anterior two thirds of the tongue; ➆: The two branches of the vestibulocochlear nerve: vestibular nerve and cochlear nerve. (Abbreviations: DCN – dorsal cochlear nucleus; DRG – dorsal root ganglia; IC – inferior colliculus; ICVX - ventrolateral border region of IC; mesenc. ncl. –mesencephalic nucleus; Cu – cuneate nucleus; Gr – gracile nucleus; principl. ncl. – principle nucleus; SG – spiral ganglion; Sp5 – spinal trigeminal nucleus; Sp5C - pars caudalis of Sp5; Sp5I - pars interpolaris of Sp5; Sp5O - pars oralis of Sp5; Subncl. gelatin. - subnucleus gelatinosus; subncl. magnocell. – subnucleus magnocellularis; subncl. marginal. – subnucleus marginalis; superfic. layer – superficial layer; TG trigeminal ganglion; VG – vestibular ganglion; VCN - ventral cochlear nucleus).

Figure 2

Spinal trigeminal nucleus, dorsal column and lateral reticular formation project to the CN. (A) –(G): Retrograde labeling in the brainstem after an injection of biotinylated dextran amine into the CN. (A) Photomicrograph of the injection site. The injection site is virtually restricted to granule cell domain of the PVCN. (B) – (D): Drawings of 1 mm transverse sections across the medulla. Each dot represents one labeled neuron. The labeled neurons are located primarily in the ipsilateral Sp5I and Sp5C. Very few labeled cells, if any, are located in the subnucleus gelatinosus (D). Labeled neurons are also found in the medullar reticular formation (RVL and LPGi, C), inferior olive (IO, C), and dorsal column nuclei (Gr and Cu, D). Projection neurons in Sp5 have either polygonal or elongated somata (E). Projection neurons in dorsal column nuclei and reticular formation are multipolar (F and G). (H): Terminal labeling in the CN after placement of an anterograde tracer into Sp5I. Most Sp5 fibers enter the CN via the DAS/IAS and terminate primarily in the granule cell domain (grey shaded), but also in deep DCN. Each dot represents one to three labeled terminal endings. Scale bars = 25 μm (E – G). (Abbreviations: CN – cochlear nucleus; Cu – cuneate nucleus; DAS - dorsal acoustic striae; DCN - dorsal cochlear nucleus; GCD - granule cell domain; Gr – gracile nucleus; IAS - intermediate acoustic striae; IO - inferior olive; LPGi - lateral paragigantocellular reticular nucleus; PVCN - posteroventral cochlear nucleus; RVL - rostral ventrolateral reticular formation; subncl. gelatin. - subnucleus gelatinosus; Sp5 – spinal trigeminal nucleus; Sp5C -pars caudalis of Sp5; Sp5I - pars interpolaris of Sp5; Sp5O - pars oralis of Sp5). (Adapted with permission from Shore & Zhou, 2006)

Figure 3

VGLUT1 and VGLUT2 show distinct expression in the CN. (A): Western blot analysis of proteins from CN and cerebellum (CB) with anti-VGLUT1 and anti-VGLUT2 antibodies. Anti-VGLUT1 antibody is recognized a single band at ~60 kDa, and anti-VGLUT2 antibody is recognized a single band at ~65 kDa, corresponding to the molecular weights predicted for VGLUT1 and VGLUT2, respectively. Molecular weight standards are indicated at left (kDa). (B): VGLUT1-ir and VGLUT2-ir in the cerebellar cortex, as a positive control (M, molecular layer; P, Purkinje cell layer; G, granular layer). (C): VGLUT1-ir in the CN at low magnification (x10). VGLUT1 is intensely expressed in DCN1 and VCNm; weak to moderate VGLUT1-ir is found in the shell and DCN2; weak VGLUT1-ir is seen in DCN3. (D): VGLUT2-ir in the CN at low magnification (x10). VGLUT2 is expressed predominantly in the shell; moderate VGLUT2-ir is found in DCN2; very weak to weak staining is found in DCN1, VCNm, and DCN3. Scale bars = 50 μm in (B); 0.5 mm in (C), (D). (Adapted with permission from Zhou et al., 2007)

Figure 4

Co-labeling of VGLUT1-ir and VGLUT2-ir with terminal endings of SP5 and auditory nerve in the CN (n=2). (A, B) Percentages of SP5 terminals (A) and auditory nerve terminals (ANF, (B)) co-labeling with VGLUT1-ir (black columns) and VGLUT2-ir (white columns). (A) About 50% of Sp5 mossy fibers (m) and 12% of small Sp5 boutons (b) colabeled with VGLUT2. Significantly fewer mossy fibers and boutons colabeled with VGLUT1 (paired t-test, P < 0.05); 23.6% ± 1% of total Sp5 terminal endings (mb, both mossy fibers and boutons) colabeled with VGLUT2, which is significantly greater than the endings colabeled with VGLUT1 (2% ± 0.1%; paired t-test, P < 0.05). (B) In contrast, many labeled ANF terminals colocalized with VGLUT1 in the VCNm (79.5% ± 7% endbulb-like terminals (e), 43.0% ± 3% bouton terminals (b)) as well as in the DCN3 (26.0% ± 5%). Neither ANF endbulb-like terminals nor small boutons were colocalized with VGLUT2. Error bars represent SEM. Asterisks indicate significant differences (see text). (C) High-magnification confocal images (×63) showing colocalization of anterogradely labeled Sp5 terminal endings with VGLUT2-ir in the small cell cap (SCC) of the CN. Green, VGLUT-ir; red, Sp5 labeling; yellow, double-labeled terminals. Images were obtained from Z projections of stacks of serial 1-μm confocal images. Insets show a single 1-μm confocal image. Mossy fibers are labeled with BDA from Sp5 and VGLUT2 in the shell. Colocalization of Sp5 MFs with VGLUT2-ir is indicated by arrowhead in C3. (Abbreviations: m – mossy fibers; b -boutons; mb - total (mossy fibers and boutons); e - endbulb-like terminals). (Adapted with permission from Zhou et al., 2007)

Figure 5

Electrical stimulation of the trigeminal ganglion elicits inhibitory (In), excitatory (E) and mixed excitatory–inhibitory (E/In) responses of dorsal cochlear nucleus neurons. (A) Post-stimulus time histogram (PSTH) for In type response. Arrow indicates stimulus onset. Inhibition occurs with a latency around 20 ms and lasts for approximately 70 ms. (B) PSTH for E type response, which occurs with a latency of approximately 15 ms and lasts for around 25 ms, returning to the pre-stimulation spike rate. (C) PSTH for E/In type response. Excitation with a shorter latency than B is followed by inhibition that recovers after approximately 20 ms. Current level of trigeminal ganglion stimulation: 80 μA; bin width: 1 ms; 200 presentations. Responses are from sorted single units in the fusiform cell layer. (Adapted with permission from Shore, 2005)

Figure 6

Neurons in the VCN respond to trigeminal stimulation with single- or multipeaked excitatory discharges. (A to F): PSTHs of single unit responses to trigeminal ganglion stimulation (50μA), arrows indicate onset of trigeminal ganglion stimulation at 0.025ms. One, two or more peaks of excitation are seen, lasting for up to 80 ms. Some neurons show chopped discharges at the beginning (A, B, F) or for the entire duration of their response (F). (Adapted with permission from Shore at al., 2003)

Figure 7

In some VCN units an excitatory response is followed by a depression of SR, that can last for 100–200 ms. Shown are PSTHs of single unit responses to trigeminal ganglion stimulation, arrows indicate onset of trigeminal ganglion stimulation (0.025ms). (Adapted with permission from Shore at al., 2003)

Figure 8

Trigeminal ganglion stimulation suppresses acoustically evoked responses in many DCN neurons. (A) Post-stimulus time histograms (PSTHs) of a single unit responding to a broadband noise (BBN, 50dB SPL, 100 ms). (B) This unit shows a buildup response to a best frequency tone burst (50-ms, onset at 0 ms, bin width: 1ms; 100 repetitions). (C) PSTH of the bimodal response of the same unit as in (A): electrical stimulation of the trigeminal ganglion (80 μA; 100 μs/phase) precedes the BBN noise stimulus by 5ms (dt). Arrow indicates onset of electrical stimulation at 95 ms; solid bar indicates 100 ms duration of BBN. PSTHs were calculated for 200 presentations, with bin width, 0.5 ms. Multisensory integration to the bimodal stimulus is calculated for times 100–150 and 150–200 ms (inset in (B)). Multisensory integration occurs as bimodal enhancement (positive percentages; BE=[(Bi−T−A)/T+A)] × 100, Bi: response rate to the bimodal stimulation, T and A: response rates to the unimodal trigeminal or acoustic stimulation respectively) or bimodal supression (negative percentages; BS=[(Bi−Uni_max)/Uni_max] × 100, Bi: response rate to the bimodal stimulation, Uni_max: response rate to the maximal effective unimodal stimulation; suppression occurs when BS<0). Suppression of more than 50% occurs during the period 150–200 ms but not during the period 100–150 ms in this unit, indicating a delayed maximal suppression. (Adapted with permission from Shore, 2005)

Figure 9

In some units DCN units trigeminal ganglion stimulation enhances responses to sound. Design of figure as Figure 8. (A) Unimodal stimulation: PSTH of a single unit responding to a broadband noise (BBN) stimulus (50 dB SPL, 100 ms). (B) Buildup PSTH of the same unit’s response to a 50-ms, best frequency tone burst. 1ms bin width; 100 repetitions; tone onset at 0 ms. (C) Bimodal stimulation: BBN noise stimulus is preceded by 5ms with an electrical stimulation of the trigeminal ganglion (80 μA; 100 μs/phase). 200 presentations. Bin width, 0.5 ms. Enhancement of almost 200% occurs during the period 150–200 ms and enhancement of almost 100% occurs during the period 100–150 ms in this unit, indicating a more rapid effect than demonstrated for the suppression in Fig. 8. The enhancement lasts for the duration of the stimulus. (Adapted with permission from Shore, 2005)

Figure 10

The temporal fine structure of acoustically evoked responses in the DCN is altered by trigeminal ganglion stimulation. Design of figure as for Figure 8. (A) Unimodal stimulation: PSTH of a single unit responding to a broadband noise (BBN) stimulus (50 dB SPL, 100 ms). (B) pauser-chopper PSTH of the same unit’s response to a 50-ms, best frequency toneburst. 1ms bin width; 100 repetitions; tone onset at 0 ms. (C) Bimodal stimulation: BBN noise stimulus is preceded by 5ms with an electrical stimulation of the trigeminal ganglion (80 μA; 100 μs/phase). 200 presentations. Bin width, 0.5 ms. Slight suppression occurs during the period 150–200 ms and enhancement of almost 70% occurs during the period 100–150 ms in this unit, with the ultimate effect producing a reversal of the temporal pattern evoked by the BBN after trigeminal stimulation. (Adapted with permission from Shore, 2005)

Figure 11

The predominant effect of bimodal integration in the IC is suppression. Responses to broad band noise (BBN) are suppressed due to trigeminal ganglion stimulation. (A) Post-stimulus time histogram (PSTH) of a single unit to electrical stimulation alone at 50 μA: this neuron does show no response to trigeminal stimulation. (B) PSTH of the same neuron to BBN at 30 dB SPL. (C) Responses to BBN are suppressed when paired with trigeminal stimulation with 50 μA. The solid bar indicates the duration of the BBN burst. The arrow indicates the onset of the electrical stimulus. Bin width 1 ms, 100 presentations. (Adapted with permission from Jain & Shore, 2006)

Figure 12

Bimodal supression in neurons of the ICx. Bar diagrams demonstrating multisensory integration in five ICx units. S, unimodal acoustic stimulation (BBN, 40 dB SPL); E, unimodal somatosensory stimulation (electrical stimulation of trigeminal nucleus with 50 μA); S + E, algebraic sum of responses to acoustic and electrical stimulation; SE, actually observed response to combined trigeminal-BBN stimulation. Bimodal suppression is quantified with the BS index (see legend figure 8): responses to bimodal stimulaton (SE) are smaller than those redicted by summing individual unimodal responses (S + E), resulting in negative BS indices, which indicates bimodal suppression. (Adapted with permission from Jain & Shore, 2006)

Figure 13

Thresholds to trigeminal stimulation decrease following noise damage. Mean thresholds for all response types to trigeminal ganglion stimulation are decreased one week and two weeks after noise exposure. Stars indicate significant differences (one week: E, p=0.021; E/In, p<0.001; In, p<0.001, two weeks: E/in, p=0.003). Error bars indicate +/− 1 standard error. (Adapted with permission from Shore et al., 2007)

Figure 14

Mean spontaneous rates (SR) for DCN single units one and two weeks after noise exposure at 120 dB SPL. The distribution of SRs by responses to trigeminal stimulation indicated that only units with E and E/I responses to trigeminal stimulation showed increased SRs after noise exposure. Units with In or no responses did not show increased SR after noise damage. (Adapted with permission from Shore et al., 2007)