Abstract and Introduction
Abstract
Transcranial direct current stimulation (tDCS) has been proposed as a potential intervention for subjective tinnitus, but supporting evidence remains limited. We aimed to investigate the effect of anodal high-definition tDCS of the left temporal area and right dorsolateral prefrontal cortex on tinnitus severity.
This double-blind randomized controlled trial included 77 patients (age range 18–79, 43 male) with chronic subjective tinnitus as their primary complaint. Thirty-eight subjects received six consecutive sessions of dual-site sequential high-definition-tDCS with electrodes positioned over the left temporal area and right dorsolateral prefrontal cortex. Both areas were stimulated for 15 min per session, with total stimulation time amounting to 30 min. Thirty-nine subjects received sham stimulation. The primary outcome measure was the change in tinnitus severity, as evaluated by the Tinnitus Functional Index, from baseline to a follow-up visit at 8 ± 2 weeks after treatment completion. Secondary outcomes included changes in perceived tinnitus loudness, as measured with a visual analogue scale and a tinnitus matching procedure, as well as scores on the Hospital Anxiety and Depression Scale, and the Hyperacusis Questionnaire.
No differences in Tinnitus Functional Index change scores were identified between the active treatment and sham control groups (linear regression: P = 0.86). The Tinnitus Functional Index scores decreased significantly over time in both groups (P = 0.0012), indicating the presence of a considerable placebo effect. These change scores were significantly influenced by sex (linear regression: P = 0.037) and baseline symptoms of anxiety (linear regression: P = 0.049) in both groups. In general, Tinnitus Functional Index scores decreased more profoundly in males and in subjects with a higher degree of anxiety at baseline. None of the included secondary measures differed significantly between experimental arms.
Our results suggest that dual-site sequential high-definition-tDCS of the left temporal area and right dorsolateral prefrontal cortex does not alleviate tinnitus severity. Interestingly, in our study population, fluctuations in tinnitus severity were influenced by gender and concurrent mental condition. It is therefore important to take these factors into account when conducting or planning randomized controlled trials in tinnitus populations.
Introduction
Tinnitus, defined as the perception of a sound with no corresponding external source, is a highly prevalent symptom present in 12 to 30% of the worldwide adult population.[1,2] Whereas some subjects suffer from objective tinnitus and perceive sounds generated by physiological events within the body, the large majority of patients experience subjective tinnitus, perceiving a sound without any corresponding sound source. The severity of tinnitus and its accompanying symptoms varies greatly. Subjects suffering from tinnitus may experience one or a combination of a plethora of accompanying non-specific symptoms, such as annoyance, irritability, anxiety, depression, hyperacusis, hearing impairment, insomnia and cognitive difficulties.[3–6] An estimated 1% of the total population perceives their tinnitus as a significant burden with a considerable impact on quality of life.[2]
There is no curative treatment for tinnitus, and currently, the only evidence-based tinnitus management strategy is cognitive behavioural therapy (CBT).[7,8] Psycho-social treatment options such as CBT are indeed able to reduce tinnitus-associated distress. However, they cause little or no reduction of the underlying tinnitus loudness, and evidence for their long-term effects is lacking. The success of other tinnitus treatments often depends on the presence and severity of accompanying symptoms. For instance, patients for whom tinnitus is paired with varying degrees of hearing loss may experience significant tinnitus relief when using hearing aids, cochlear implants or auditory brainstem implants.[9–12] Meanwhile, subjects with concomitant cervical or temporomandibular dysfunctions can achieve beneficial results with physical therapy such as orofacial treatment.[13] Thus, the large heterogeneity in tinnitus presentation requires a personalized, patient-tailored treatment plan.[14] Overall, existing management strategies more often target accompanying symptoms other than the underlying pathophysiology of the tinnitus percept itself.
While tinnitus is often preceded by some form of cochlear damage, the relationship between tinnitus and hearing loss is not straightforward. A dominant theory for the formation of tinnitus is the central gain hypothesis, which postulates that reduced somatosensory input leads to amplified spontaneous firing at the level of the auditory neurons, which is then relayed to higher order nuclei and the auditory cortex.[15,16] This hypothesis has been demonstrated in animal models of tinnitus[17,18] and is consistent with findings of hyperactivity in auditory cortex illustrated by human MRI and EEG studies.[19,20] However, recent research has offered important counterpoints to this bottom-up central gain hypothesis, such as the relative absence of tonotopic map changes in auditory cortex of hearing-impaired individuals with tinnitus.[21] Consequently, researchers have begun proposing alternative or additional theoretical models of tinnitus generation. One hypothesis is the predictive coding theory, which posits that the perception of tinnitus relies on higher perceptual networks recognizing auditory activity as an auditory entity instead of noise, regardless of the level of cochlear damage.[22] Overall, the influence of top-down processes contributing to the tinnitus percept is increasingly being recognized, as the importance of other cortical regions such as prefrontal cortex, parahippocampus, anterior cingulate cortex and insula becomes clear.[19,23–25]
Overall, a large body of evidence on tinnitus-related aberrant activity and connectivity in both auditory and non-auditory brain areas exists. As the extent of these cortical irregularities is illuminated, researchers have begun exploring the targeting of such aberrant brain activity as a therapeutic option.[26,27] Acts of modifying underlying neural activity, often with the aim of achieving a therapeutic benefit, fall under the heading of neuromodulation. The induction of neuroplastic changes via neuromodulation may interrupt the observed aberrant neural activity and, thus, alter or reduce the tinnitus percept.[28] Non-invasive neuromodulation can be performed using several different modalities. For instance, repeated electromagnetic pulses may be delivered by a coil producing magnetic fields in a procedure known as repetitive transcranial magnetic stimulation (rTMS). Some studies have demonstrated that rTMS is capable of suppressing tinnitus symptoms, but its therapeutic effect is often partial and transient.[29,30] A potential alternative approach is the direct delivery of low-intensity electric currents to the brain via scalp electrodes. The technique using direct currents is known as transcranial direct current stimulation (tDCS). Immediate effects of tDCS are usually less marked than those elicited by rTMS, as this technique does not elicit action potentials, but rather modulates subthreshold cortical excitability. The mechanisms of action of tDCS remain to be elucidated. Initial investigations of tDCS of the motor cortex have led to the assumption that anodal tDCS increases and cathodal tDCS decreases the excitability of the underlying cortex.[31] However, this does not function as a general rule, as numerous factors have been shown to influence tDCS polarity effects, including dendritic orientation, baseline activity, and current intensity.[32] Despite the considerable degree of uncertainty regarding the exact mechanisms of action, tDCS has been suggested as a potential therapeutic application in many different domains,[33] and researchers generally agree that the weak currents delivered by tDCS are able to influence oscillatory neural behaviour and affect cortical connectivity.[34,35]
In existing trials investigating tDCS as an experimental treatment for tinnitus, electrodes have often been placed over the left temporal area (LTA), which comprises the auditory cortex. Initial studies applying anodal tDCS over the LTA found preliminary results showing transient tinnitus suppression in up to 40% of participants.[36,37] However, more recent trials have not been able to conclusively replicate these findings.[38,39] A different area of interest for tDCS in tinnitus trials is the right dorsolateral prefrontal cortex (rDLPFC). Stimulation of this area has been proposed to strengthen deficient inhibitory top-down mechanisms, as well as interfere with the emotional response to the tinnitus percept.[40] Pilot studies applying anodal tDCS over the rDLPFC reported promising effects,[41–43] but the evidence remains too preliminary to make definitive recommendations.[33] A direct comparison between stimulation of both areas yielded no difference in effect, although it is not unthinkable that the targeting of different cortical areas acts on the tinnitus percept via different mechanisms.[44] The recent introduction of high-definition (HD) tDCS, which uses small ring electrodes allowing for more focal stimulation, has opened up the possibility of stimulating both areas within one session.[45] Such a dual-site stimulation protocol may have more profound and longer-lasting effects on underlying cortical excitability.[44,46,47] However, this has not yet been investigated in a tinnitus population.
Overall, current trials into the effects of tDCS on tinnitus are characterized by a considerable degree of variability and a low quality of evidence. Many of the published studies lack a sham arm, although placebo effects in patients with tinnitus are well documented and should undoubtedly be taken into account.[48,49] Several sham-controlled studies have investigated the effect of only one tDCS session on tinnitus,[50,51] although it has been suggested that a single session of tDCS is not sufficient to elicit long-term effects.[43] Some sham-controlled trials investigating the effects of multiple sessions of tDCS on tinnitus exist, but they are characterized by small sample sizes (generally, 11 to 15 subjects are included in each group) and a high degree of between-study heterogeneity concerning electrode placement and used tDCS protocol.[38,39,41,52] Summarizing the existing evidence, a recent meta-analysis found a small to moderate, but ultimately non-significant, effect of active versus sham tDCS on tinnitus.[49] The authors found no compelling evidence that active tDCS diminishes tinnitus symptoms, but nevertheless reported a clinically significant mean change of tinnitus standardized questionnaire scores. Thus, some uncertainty regarding potential tDCS effects on tinnitus still remains.
We performed a randomized controlled trial into the effects of dual-site HD-tDCS of the LTA and rDPLFC in a well-defined study population of patients with chronic subjective tinnitus as their primary complaint. Our primary aim was to investigate the therapeutic effect of HD-tDCS on tinnitus severity and its impact on quality of life, as measured by the Tinnitus Functional Index (TFI). In addition, we examined HD-tDCS effects on secondary outcomes including tinnitus loudness, hyperacusis and concurrent symptoms of anxiety and depression.
Brain. 2022;145(12):4222-4231. © 2022 Oxford University Press
