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Notwithstanding advances with low-intensity transcranial electrical stimulation (tES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. To measure electric fields magnitude and their effects on neuronal firing rate of hippocampal neurons in freely moving rats, and to establish calibrated computational models of current flow. Current flow models were calibrated on electric field measures in the motor cortex (n = 2 anesthetized rats) and hippocampus. A Neuropixels 2.0 probe with 384 channels was used in an in-vivo rat model of tES (n = 4 freely moving and 2 urethane anesthetized rats) to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 μA of applied skull currents). Electric fields of as low as 0.35 V/m (0.25–0.47) acutely modulated average firing rate in the hippocampus. At these intensities, firing rate effects increased monotonically with electric field intensity at a rate of 11.5 % per V/m (7.2–18.3). For the majority of excitatory neurons, firing increased for soma-depolarizing stimulation and diminished for soma-hyperpolarizing stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. In awake animals, electric fields modulate spiking rate above levels previously observed in vitro. Firing rate effects are likely mediated by somatic polarization of pyramidal neurons. We recommend that all future rodent experiments directly measure electric fields to insure rigor and reproducibility. • tES can acutely affect neuronal firing rate at clinically relevant electric field intensities in behaving rats. • Average firing rate effects increased monotonically with electric field intensity. • Polarity of the effect is consistent with somatic polarization in pyramidal cells and with a network effect on interneurons. [ABSTRACT FROM AUTHOR]

Motor learning experiments with transcranial direct current stimulation (tDCS) at 2 mA have produced mixed results. We hypothesize that tDCS boosts motor learning provided sufficiently high field intensity on the motor cortex. In a single-blinded design, 108 healthy participants received either anodal (N = 36) or cathodal (N = 36) tDCS at 4 mA total, or no stimulation (N = 36) while they practiced a 12-min sequence learning task. Anodal stimulation was delivered across four electrode pairs (1 mA each), with anodes above the right parietal lobe and cathodes above the right frontal lobe. Cathodal stimulation, with reversed polarities, served as an active control for sensation, while the no-stimulation condition established baseline performance. fMRI-localized targets on the primary motor cortex in 10 subjects were used in current flow models to optimize electrode placement for maximal field intensity. A single electrode montage was then selected for all participants. We found a significant difference in performance with anodal vs. cathodal stimulation (Cohen's d = 0.71) and vs. no stimulation (d = 0.56). This effect persisted for at least 1 h, and subsequent learning for a new sequence and the opposite hand also improved. Sensation ratings were comparable in the active groups and did not exceed moderate levels. Current flow models suggest the new electrode montage can achieve stronger motor cortex polarization than alternative montages. The present paradigm shows a medium to large effect size and is well-tolerated. It may serve as a go-to experiment for future studies on motor learning and tDCS. • TDCS resulted in a lasting boost of concurrent learning with medium to large effect sizes. • Subsequent learning was also improved, possibly indicating a form of meta-learning. • A novel electrode montage with 1 mA through each of 4 + 4 electrodes was well-tolerated. • Delivering 4 mA through 4 + 4 electrode montage results in an estimated four-fold increase in intensity over standard practice. [ABSTRACT FROM AUTHOR]

Electric fields generated during direct current stimulation (DCS) are known to modulate activity-dependent synaptic plasticity in-vitro. This provides a mechanistic explanation for the lasting behavioral effects observed with transcranial direct current stimulation (tDCS) in human learning experiments. However, previous in-vitro synaptic plasticity experiments show relatively small effects despite using strong fields compared to what is expected with conventional tDCS in humans (20 V/m vs. 1 V/m). There is therefore a need to improve the effectiveness of tDCS at realistic field intensities. Here we leverage the observation that effects of learning are known to accumulate over multiple bouts of learning, known as spaced learning. We propose that effects of DCS on synaptic long-term potentiation (LTP) accumulate over time in a spaced learning paradigm, thus revealing effects at more realistic field intensities. We leverage a standard model for spaced learning by inducing LTP with repeated bouts of theta burst stimulation (TBS) in hippocampal slice preparations. We studied the cumulative effects of DCS paired with TBS at various intensities applied during the induction of LTP in the CA1 region of rat hippocampal slices. As predicted, DCS applied during repeated bouts of theta burst stimulation (TBS) resulted in an increase of LTP. This spaced learning effect is saturated quickly with strong TBS protocols and stronger fields. In contrast, weaker TBS and the weakest electric fields of 2.5 V/m resulted in the strongest relative efficacies (12% boost in LTP per 1 V/m applied). Weak DCS causes a relatively strong cumulative effect of spaced learning on synaptic plasticity. Staturarion may have masked stronger effects sizes in previous in-vitro studies. Relative effect sizes of DCS are now closer in line with human tDCS experiments. • DCS applied during repeated bouts of TBS has cumulative effect over LTP. • Spaced learning effect saturates quickly with strong TBS protocols and stronger fields. • Weaker TBS and the weakest electric fields of 2.5 V/m result in the strongest relative efficacies. [ABSTRACT FROM AUTHOR]

Skin sensation is the primary factor limiting the intensity of transcranial electrical stimulation (tES). It is well established that different waveforms generate different sensations, yet transcranial stimulation has been limited to a relatively small number of prototypical waveforms. We explore whether alternative stimulation waveforms could substantially reduce skin sensation and thus allow for stronger intensities in tES. We systematically tested a range of waveforms in a series of 6 exploratory experiments stimulating human adults on the forearm and in one instance on the head. Subjects were asked to rate skin sensation level on a numerical scale from "none" to "extreme". High frequency (>1 kHz) monophasic square wave stimulation was found to decrease in sensation with increasing duty cycle, baseline, and frequency, but the sensation was never lower than for constant current stimulation. For the purpose of injecting a net direct current (DC), a constant current is optimal. For stimulation with alternating current (AC), sensation decreased with increasing frequency, consistent with previous reports. Amplitude modulation did not reduce sensation below stimulation with constant AC amplitude, and biphasic square waveforms produced higher sensation levels than biphasic sinusoidal waveforms. Furthermore, for DC stimulation, sensation levels on the arm were similar to those reported on the head. Our comparisons of various waveforms for monophasic and biphasic stimulation indicate that conventional DC and AC waveforms may provide the lowest skin sensations levels for transcutaneous electrical stimulation. These results are likely generalizable to tES applications. • Substitute waveforms for monophasic stimulation do not reduce skin sensation. • Substitute waveforms for biphasic stimulation do not reduce skin sensation. • Conventional waveforms elicit minimal skin sensation. • Skin sensation of direct current stimulation is the same on the head and the arm. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (DCS) has lasting effects that may be explained by a boost in synaptic long-term potentiation (LTP). We hypothesized that this boost is the result of a modulation of somatic spiking in the postsynaptic neuron, as opposed to indirect network effects. To test this directly we record somatic spiking in a postsynaptic neuron during LTP induction with concurrent DCS. We performed rodent in-vitro patch-clamp recordings at the soma of individual CA1 pyramidal neurons. LTP was induced with theta-burst stimulation (TBS) applied concurrently with DCS. To test the causal role of somatic polarization, we manipulated polarization via current injections. We also used a computational multi-compartment neuron model that captures the effect of electric fields on membrane polarization and activity-dependent synaptic plasticity. TBS-induced LTP was enhanced when paired with anodal DCS as well as depolarizing current injections. In both cases, somatic spiking during the TBS was increased, suggesting that evoked somatic activity is the primary factor affecting LTP modulation. However, the boost of LTP with DCS was less than expected given the increase in spiking activity alone. In some cells, we also observed DCS-induced spiking, suggesting DCS also modulates LTP via induced network activity. The computational model reproduces these results and suggests that they are driven by both direct changes in postsynaptic spiking and indirect changes due to network activity. DCS enhances synaptic plasticity by increasing postsynaptic somatic spiking, but we also find that an increase in network activity may boost but also limit this enhancement. • DCS increases somatic spiking in the postsynaptic neuron. • DCS enhances Hebbian LTP. • DCS can induce network activity. • DCS-induced network activity may limit potentiation of the synaptic efficacy. [ABSTRACT FROM AUTHOR]

Temporal interference (TI) stimulation of the brain generates amplitude-modulated electric fields oscillating in the kHz range with the goal of non-invasive targeted deep brain stimulation. Yet, the current intensities required in human (sensitivity) to modulate deep brain activity and if superficial brain region are spared (selectivity) at these intensities remains unclear. We developed an experimentally constrained theory for TI sensitivity to kHz electric field given the attenuation by membrane low-pass filtering property, and for TI selectivity to deep structures given the distribution of modulated and unmodulated electric fields in brain. The electric field threshold to modulate carbachol-induced gamma oscillations in rat hippocampal slices was determined for unmodulated 0.05–2 kHz sine waveforms, and 5 Hz amplitude-modulated waveforms with 0.1–2 kHz carrier frequencies. The neuronal effects are replicated with a computational network model to explore the underlying mechanisms, and then coupled to a validated current-flow model of the human head. Amplitude-modulated electric fields are stronger in deep brain regions, while unmodulated electric fields are maximal at the cortical regions. Both experiment and model confirmed the hypothesis that spatial selectivity of temporal interference stimulation depends on the phasic modulation of neural oscillations only in deep brain regions. Adaptation mechanism (e.g. GABA b) enhanced sensitivity to amplitude modulated waveform in contrast to unmodulated kHz and produced selectivity in modulating gamma oscillation (i.e. Higher gamma modulation in amplitude modulated vs unmodulated kHz stimulation). Selection of carrier frequency strongly affected sensitivity to amplitude modulation stimulation. Amplitude modulated stimulation with 100 Hz carrier frequency required ∼5 V/m (corresponding to ∼13 mA at the scalp surface), whereas, 1 kHz carrier frequency ∼60 V/m (∼160 mA) and 2 kHz carrier frequency ∼80 V/m (∼220 mA) to significantly modulate gamma oscillation. Sensitivity is increased (scalp current required decreased) for theoretical neuronal membranes with faster time constants. The TI sensitivity (current required at the scalp) depends on the neuronal membrane time-constant (e.g. axons) approaching the kHz carrier frequency. TI selectivity is governed by network adaption (e.g. GABA b) that is faster than the amplitude-modulation frequency. Thus, we show neuronal and network oscillations time-constants determine the scalp current required and the selectivity achievable with TI in humans. • We explain sensitivity and selectivity to temporal interference stimulation using in vitro model of hippocampal gamma oscillations. • The applied current required (sensitivity) depends on the neuronal membrane time-constant approaching the kHz carrier frequency of temporal interference stimulation. • This selectivity is governed by network adaption mechanism. [ABSTRACT FROM AUTHOR]

There is evidence that transcranial direct current stimulation (tDCS) can improve learning performance. Arguably, this effect is related to long term potentiation (LTP), but the precise biophysical mechanisms remain unknown. We propose that direct current stimulation (DCS) causes small changes in postsynaptic membrane potential during ongoing endogenous synaptic activity. The altered voltage dynamics in the postsynaptic neuron then modify synaptic strength via the machinery of endogenous voltage-dependent Hebbian plasticity. This hypothesis predicts that DCS should exhibit Hebbian properties, namely pathway specificity and associativity. We studied the effects of DCS applied during the induction of LTP in the CA1 region of rat hippocampal slices and using a biophysical computational model. DCS enhanced LTP, but only at synapses that were undergoing plasticity, confirming that DCS respects Hebbian pathway specificity. When different synaptic pathways cooperated to produce LTP, DCS enhanced this cooperation, boosting Hebbian associativity. Further slice experiments and computer simulations support a model where polarization of postsynaptic pyramidal neurons drives these plasticity effects through endogenous Hebbian mechanisms. The model is able to reconcile several experimental results by capturing the complex interaction between the induced electric field, neuron morphology, and endogenous neural activity. These results suggest that tDCS can enhance associative learning. We propose that clinical tDCS should be applied during tasks that induce Hebbian plasticity to harness this phenomenon, and that the effects should be task specific through their interaction with endogenous plasticity mechanisms. Models that incorporate brain state and plasticity mechanisms may help to improve prediction of tDCS outcomes. • DCS boost LTP and Hebbian associativity, while maintaining pathway specificity. • Effects are consistent with somatic polarization of postsynaptic pyramidal cells. • A computational model captures the dependence on endogenous synaptic activity. • tDCS should be applied during training that induces Hebbian plasticity. • Effects should be specific to trained tasks. [ABSTRACT FROM AUTHOR]

Narratives can synchronize neural and physiological signals between individuals, but the relationship between these signals, and the underlying mechanism, is unclear. We hypothesized a top-down effect of cognition on arousal and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size, and heart rate were all associated with anterior-central brain signals. Together, these results suggest bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal. [Display omitted] • Listening to narratives modulates eye movements • Heart rate fluctuations precede pupil size fluctuations and anterior-central neural activity • Breathing modulates pupil size, suggesting causal effect on central arousal • Rhythmic saccades can entrain heart beats When we listen to a story, our body is integrally involved in the experience. Madsen and Parra provide evidence for a bidirectional link between body and brain by analyzing electroencephalography, pupil size, heart rate, and eye movements while subjects listen to narratives and during controlled interventions that modulate autonomic signals. [ABSTRACT FROM AUTHOR]

Abstract To reach a deep target in the brain with transcranial electric stimulation (TES), currents have to pass also through the cortical surface. Thus, it is generally thought that TES cannot achieve focal deep brain stimulation. Recent efforts with interfering waveforms and pulsed stimulation have argued that one can achieve deeper or more intense stimulation in the brain. Here we argue that conventional transcranial stimulation with multiple current sources is just as effective as these new approaches. The conventional multi-electrode approach can be numerically optimized to maximize intensity or focality at a desired target location. Using such optimal electrode configurations we find in a detailed and realistic head model that deep targets may in fact be strongly stimulated, with cerebro-spinal fluid guiding currents deep into the brain. Highlights • Deep targets can be reached with intensities comparable to the cortical surface. • Multi-electrode montages increase intensity with the same current limits per electrode. • High-definition and intersectional pulsed stimulation are largely equivalent. • Interferential stimulation is generally weaker than conventional stimulation. [ABSTRACT FROM AUTHOR]

Background Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. Objective This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. Methods The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. Results Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. Conclusions These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders. [ABSTRACT FROM AUTHOR]

Background Transcranial direct current stimulation (tDCS) has been reported to improve various forms of learning in humans. Stimulation is often applied during training, producing lasting enhancements that are specific to the learned task. These learning effects are thought to be mediated by altered synaptic plasticity. However, the effects of DCS during the induction of endogenous synaptic plasticity remain largely unexplored. Objective/Hypothesis Here we are interested in the effects of DCS applied during synaptic plasticity induction. Methods To model endogenous plasticity we induced long-term potentiation (LTP) and depression (LTD) at Schaffer collateral synapses in CA1 of rat hippocampal slices. Anodal and cathodal DCS at 20 V/m were applied throughout plasticity induction in both apical and basal dendritic compartments. Results When DCS was paired with concurrent plasticity induction, the resulting plasticity was biased towards potentiation, such that LTP was enhanced and LTD was reduced. Remarkably, both anodal and cathodal stimulation can produce this bias, depending on the dendritic location and type of plasticity induction. Cathodal DCS enhanced LTP in apical dendrites while anodal DCS enhanced LTP in basal dendrites. Both anodal and cathodal DCS reduced LTD in apical dendrites. DCS did not affect synapses that were weakly active or when NMDA receptors were blocked. Conclusions These results highlight the role of DCS as a modulator, rather than inducer of synaptic plasticity, as well as the dependence of DCS effects on the spatial and temporal properties of endogenous synaptic activity. The relevance of the present results to human tDCS should be validated in future studies. [ABSTRACT FROM AUTHOR]

Background Direct current stimulation (DCS) affects both neuronal firing rate and synaptic efficacy. The neuronal input/output (I/O) function determines the likelihood that a neuron elicits an action potential in response to synaptic input of a given strength. Changes of the neuronal I/O function by DCS may underlie previous observations in animal models and human testing, yet have not been directly assessed. Objective Test if the neuronal input/output function is affected by DCS Methods Using rat hippocampal brain slices and computational modeling, we provide evidence for how DCS modulates the neuronal I/O function. Results We show for the first time that DCS modulates the likelihood of neuronal firing for a given and fixed synaptic input. Opposing polarization of soma and dendrite may have a synergistic effect for anodal stimulation, increasing the driving force of synaptic activity while simultaneously increasing spiking probability at the soma. For cathodal stimulation, however, the opposing effects tend to cancel. This results in an asymmetry in the strength of the effects of stimulation for opposite polarities. Conclusions Our results may explain the asymmetries observed in acute and long term effects of transcranial direct current stimulation. [ABSTRACT FROM AUTHOR]

Unlabelled: Despite promising preliminary results in treating fibromyalgia (FM) pain, no neuromodulation technique has been adopted in clinical practice because of limited efficacy, low response rate, or poor tolerability. This phase II open-label trial aims to define a methodology for a clinically effective treatment of pain in FM by establishing treatment protocols and screening procedures to maximize efficacy and response rate. High-definition transcranial direct current stimulation (HD-tDCS) provides targeted subthreshold brain stimulation, combining tolerability with specificity. We aimed to establish the number of HD-tDCS sessions required to achieve a 50% FM pain reduction, and to characterize the biometrics of the response, including brain network activation pain scores of contact heat-evoked potentials. We report a clinically significant benefit of a 50% pain reduction in half (n = 7) of the patients (N = 14), with responders and nonresponders alike benefiting from a cumulative effect of treatment, reflected in significant pain reduction (P = .035) as well as improved quality of life (P = .001) over time. We also report an aggregate 6-week response rate of 50% of patients and estimate 15 as the median number of HD-tDCS sessions to reach clinically meaningful outcomes. The methodology for a pivotal FM neuromodulation clinical trial with individualized treatment is thus supported.Online Registration: Registered in Clinicaltrials.gov under registry number NCT01842009.Perspective: In this article, an optimized protocol for the treatment of fibromyalgia pain with targeted subthreshold brain stimulation using high-definition transcranial direct current stimulation is outlined. [ABSTRACT FROM AUTHOR]

Computational models of brain current flow during transcranial electrical stimulation (tES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), are increasingly used to understand and optimize clinical trials. We propose that broad dissemination requires a simple graphical user interface (GUI) software that allows users to explore and design montages in real-time, based on their own clinical/experimental experience and objectives. We introduce two complimentary open-source platforms for this purpose: BONSAI and SPHERES. BONSAI is a web (cloud) based application (available at neuralengr.com/bonsai) that can be accessed through any flash-supported browser interface. SPHERES (available at neuralengr.com/spheres) is a stand-alone GUI application that allow consideration of arbitrary montages on a concentric sphere model by leveraging an analytical solution. These open-source tES modeling platforms are designed go be upgraded and enhanced. Trade-offs between open-access approaches that balance ease of access, speed, and flexibility are discussed. [ABSTRACT FROM AUTHOR]

Background The importance of slow-wave sleep (SWS), hallmarked by the occurrence of sleep slow oscillations (SO), for the consolidation of hippocampus-dependent memories has been shown in numerous studies. Previously, the application of transcranial direct current stimulation, oscillating at the frequency of endogenous slow oscillations, during SWS enhanced memory consolidation for a hippocampus dependent task in humans suggesting a causal role of slowly oscillating electric fields for sleep dependent memory consolidation. Objective Here, we aimed to replicate and extend these findings to a rodent model. Methods Slow oscillatory direct transcranial current stimulation (SO-tDCS) was applied over the frontal cortex of rats during non-rapid eye movement (NREM) sleep and its effects on memory consolidation in the one-trial object-place recognition task were examined. A retention interval of 24 h was used to investigate the effects of SO-tDCS on long-term memory. Results Animals' preference for the displaced object was significantly greater than chance only when animals received SO-tDCS. EEG spectral power indicated a trend toward a transient enhancement of endogenous SO activity in the SO-tDCS condition. Conclusions These results support the hypothesis that slowly oscillating electric fields causal affect sleep dependent memory consolidation, and demonstrate that oscillatory tDCS can be a valuable tool to investigate the function of endogenous cortical network activity. [ABSTRACT FROM AUTHOR]

Heart rate has natural fluctuations that are typically ascribed to autonomic function. Recent evidence suggests that conscious processing can affect the timing of the heartbeat. We hypothesized that heart rate is modulated by conscious processing and therefore dependent on attentional focus. To test this, we leverage the observation that neural processes synchronize between subjects by presenting an identical narrative stimulus. As predicted, we find significant inter-subject correlation of heart rate (ISC-HR) when subjects are presented with an auditory or audiovisual narrative. Consistent with our hypothesis, we find that ISC-HR is reduced when subjects are distracted from the narrative, and higher ISC-HR predicts better recall of the narrative. Finally, patients with disorders of consciousness have lower ISC-HR, as compared to healthy individuals. We conclude that heart rate fluctuations are partially driven by conscious processing, depend on attentional state, and may represent a simple metric to assess conscious state in unresponsive patients. [Display omitted] • Narrative stimuli can synchronize fluctuations of heart rate between individuals • This interpersonal synchronization is modulated by attention and predicts memory • These effects on heart rate cannot be explained by modulation of respiratory patterns • Synchrony is lower in patients with disorders of consciousness Stories affect our hearts and bind us together. Pérez et al. show that attention to narratives can synchronize fluctuations of heart rate between individuals. Heart synchronization predicts memory and cannot be explained by respiration. Finally, synchrony is lower in patients with disorders of consciousness and might inform prognosis. [ABSTRACT FROM AUTHOR]

Abstract: The presence of tinnitus often coincides with hearing loss. It has been argued that reduced peripheral input leads to frequency-specific increase in neuronal gains resulting in tinnitus-related hyper-activity. Following this gain-adaptation hypothesis, impaired cochlear function should be predictive of the presence and spectral characteristics of tinnitus. To assess cochlear function, perceptual thresholds and distortion product otoacoustic emissions (DPOAEs) were measured with high frequency resolution for subjects with tinnitus and non-tinnitus control subjects (N = 29 and N = 18) with and without hearing loss. Subjects with tinnitus also provided a ‘tinnitus likeness spectrum’ by rating the similarity of their tinnitus to tones at various frequencies. On average, subjects with tinnitus had elevated thresholds, reduced DPOAE, and increased slope of the DPOAE input-output function in the range from 4 to 10 kHz. These measures were strongly correlated and were equally predictive of the presence of tinnitus. Subjects with a pronounced edge to their hearing loss profile were very likely to have tinnitus. In the group average, the tinnitus likeness spectrum was correlated with perceptual thresholds (r = 0.98, p < 0.01), confirming previous reports. For 19 of 29 of subjects, perceptual thresholds were correlated with the tinnitus likeness ratings across frequencies and this correlation was significantly improved when low input-level DPOAE were included as an additional variable (r = 0.83 ± 0.09, N = 19). Thus, cochlear function is strongly associated with the tinnitus percept and measures of cochlear function using DPOAEs provide additional diagnostic information over perceptual thresholds alone. [Copyright &y& Elsevier]