Maladaptive neural synchrony in tinnitus: origin and restoration

Abstract

Tinnitus is the conscious perception of sound heard in the absence of physical sound sources external or internal to the body, reflected in aberrant neural synchrony of spontaneous or resting-state brain activity. Neural synchrony is generated by the nearly simultaneous firing of individual neurons, of the synchronization of membrane-potential changes in local neural groups as reflected in the local field potentials, resulting in the presence of oscillatory brain waves in the EEG. Noise-induced hearing loss, often resulting in tinnitus, causes a reorganization of the tonotopic map in auditory cortex and increased spontaneous firing rates and neural synchrony. Spontaneous brain rhythms rely on neural synchrony. Abnormal neural synchrony in tinnitus appears to be confined to specific frequency bands of brain rhythms. Increases in delta-band activity are generated by deafferented/deprived neuronal networks resulting from hearing loss. Coordinated reset (CR) stimulation was developed in order to specifically counteract such abnormal neuronal synchrony by desynchronization. The goal of acoustic CR neuromodulation is to desynchronize tinnitus-related abnormal delta-band oscillations. CR neuromodulation does not require permanent stimulus delivery in order to achieve long-lasting desynchronization or even a full-blown anti-kindling but may have cumulative effects, i.e., the effect of different CR epochs separated by pauses may accumulate. Unlike other approaches, acoustic CR neuromodulation does not intend to reduce tinnitus-related neuronal activity by employing lateral inhibition. The potential efficacy of acoustic CR modulation was shown in a clinical proof of concept trial, where effects achieved in 12 weeks of treatment delivered 4-6 h/day persisted through a preplanned 4-week therapy pause and showed sustained long-term effects after 10 months of therapy, leading to 75% responders.

Keywords: brain rhythms; coordinated reset; neural plasticity; neural synchrony; tinnitus.

Figures

Figure 1

Acoustic coordinated reset (CR) neuromodulation. (A) CR neuromodulation means to deliver phase resetting stimuli to neuronal subpopulations in a spatiotemporally coordinated manner in order to induce desynchronization and eventually anti-kindling (104, 109, 110): employing the tonotopic organization of the primary auditory cortex [left, brain adapted from Chittka and Brockmann (135) with kind permission of the authors] short sinusoidal tones of different frequencies were grouped within approximately one octave around the tinnitus frequency ft (f1 = 0.77 ft, f4 = 1,40 ft) to induce a soft reset (134) of different parts of the synchronized tinnitus focus, respectively. Three CR cycles, each containing a randomized sequence of four tones (left), were followed by two silent cycles (“pause”). That pattern was repeated periodically [compare (104, 109, 110, 115)]. (B) The proof of concept study by Tass et al. (132) comprised four stimulation groups (G1–G4) and one placebo group (G5), where G2 served as active control group. Patients in groups G1, G3, and G4 were treated with acoustic CR neuromodulation, i.e., with four tones (top, f1–f4) grouped around the tinnitus frequency (ft). In all patients, ft was assessed with a pure tone matching. G3 differs only in repetition rate F (i.e., the inverse of the duration of a cycle), which was adapted to the individual EEG δ-band peak at each visit. According to computational studies, continuous online adaptation of F should be beneficial (109, 110). In all other groups, the repetition rate F was set to 1.5 Hz to target delta oscillations (109, 110). Stimulation dosage was 4–6 h/day in G1–G3 and 1 h/day in G4 and G5. For G2 in each CR cycle, a random selection of four tones (dark green: active) was taken out of 12 (middle, f1–f12) surrounding ft. For placebo stimulation (bottom, G5), a similar pattern as for G1 was used, but with down-shifted stimulation frequency fp [fp = 0.7071 ft/(2n), and fp within (300 Hz, 600 Hz)] to ensure stimulation outside the synchronized tinnitus focus. Figure from Tass et al. (132) with kind permission by the authors. Copyright by Forschungszentrum Jülich GmbH.

Figure 2

Electrophysiological effects of acoustic CR neuromodulation studied by Tass et al. (132): 3D mapping of treatment induced changes in spectral power of oscillatory EEG activity (baseline compared to 12 weeks, recorded in off-stimulation condition). To increase signal-to-noise ratio, 12 patients with bilateral tinnitus (from G1, G3, and G4, see Figure 1) were selected using a reliable-change-index (RCI) (147) applied to improvements of TF scores. Statistical non-parametric maps from sLORETA (152) provide localization of changes of δ (1–4 Hz), θ (4–8 Hz), α (8–12 Hz), β (12–30 Hz), γlow (30–48 Hz), and γhigh (52–90 Hz) spectral power. Results were superimposed onto a three-dimensional brain (first three columns) and onto a horizontal brain section (right column) of a standard anatomical template. Significantly decreased spectral power after acoustic CR neuromodulation compared to baseline is labeled blue, increased spectral power is labeled red (corrected, p < 0.05). Abbreviations: R, rostral; C, caudal; r, right; l, left. Figure from Tass et al. (132) with kind permission by the authors. Copyright by Forschungszentrum Jülich GmbH.