Loudness Dependence Of The Auditory Evoked Potential Research Articles

The Loudness Dependence of Auditory Evoked Potentials is associated with the Symptom Severity and Treatment in Boys with Attention Deficit Hyperactivity Disorder.

ObjectiveThe loudness dependence of the auditory evoked potential (LDAEP) is associated with central serotonergic neurotransmission. Recent studies have proposed that LDAEP is also influenced by dopaminergic activity. Evidence shows attention deficit hyperactivity disorder (ADHD) symptoms are associated with dopamine dysfunction. This study aimed to evaluate the relation between ADHD symptoms and LDAEP, as well as medication-mediated changes of LDAEP.MethodsA total of 38 male children (6−12 years old) with ADHD were analyzed in this study. Symptom severity was assessed using the ADHD rating scale (ARS) and the continuous performance test. To determine LDAEP, the auditory event-related potential was evaluated before medication. Changes in LDAEP were measured after 12 weeks of treatment with methylphenidate.ResultsThe subjects had a mean age of 9.24 ± 1.74 years with an average IQ of 109.4 ± 13.8. Before pharmacological treatment with methylphenidate, LDAEP was positively associated with the ARS score after adjusting for age and IQ (r = 0.592, p = 0.005). LDAEP was correlated with inattention (r = 0.522, p = 0.015) and hyperactivity-impulsivity (r = 0.6, p = 0.004). However, the LDAEP of 15 subjects decreased following methylphenidate treatment (Z = −1.988, p = 0.047).ConclusionIn boys with ADHD, LDAEP appears to be associated with symptom severity. LDAEP showed a significant association with impulsivity and inattention. Importantly, LDAEP was shown to decrease after drug treatment. Our findings support the utility of LDAEP as a noninvasive and clinically useful method to assess symptom severity in children with ADHD.

Relationship Between the Loudness Dependence of the Auditory Evoked Potential and the Severity of Suicidal Ideation in Patients with Major Depressive Disorder.

ObjectiveThe loudness dependence of the auditory evoked potential (LDAEP) is a reliable indicator that is inversely related to central serotonergic activity, and recent studies have suggested an association between LDAEP and suicidal ideation. This study investigated differences in LDAEP between patients with major depressive disorder and high suicidality and those with major depressive disorder and low suicidality compared to healthy controls.MethodsThis study included 67 participants 23 patients with major depressive disorder with high suicidality (9 males, mean age 29.3 ± 15.7 years, total score of SSI-BECK ≥ 15), 22 patients with major depressive disorder with low suicidality (9 males, mean age 42.2 ± 14.4 years, total score of SSI-BECK ≤ 14), and 22 healthy controls (11 males, mean age 31.6 ± 8.7 years). Participants completed the following assessments Patient Health Questionnaire-9, Beck Depression Inventory-II, Beck Scale for Suicidal ideation, State Anxiety Scale of the State-Trait Anxiety Inventory, Beck Anxiety Inventory, and LDAEP (measured at electrode Cz).ResultsThere were no sex-related differences among groups (p = 0.821). The high-suicidality group exhibited significantly higher LDAEP compared to the low-suicidality group (0.82 ± 0.79 vs. 0.26 ± 0.36, p = 0.014). No significant differences were found between the control and high-suicidality (p = 0.281) or the control and low-suicidality groups (p = 0.236).ConclusionLDAEP was applied to demonstrate the association between serotonergic activity and suicidal ideation and suicide risk in major depression and may be a candidate of biological marker for preventing suicide in this study.

Serotonergic Dysfunction in Patients with Bipolar Disorder Assessed by the Loudness Dependence of the Auditory Evoked Potential

ObjectiveThe loudness dependence of the auditory evoked potential (LDAEP) is suggested to be a marker of serotonin system function. This study explored the LDAEP of multiple mood statuses (depression, mania, and euthymia) and its clinical implication in bipolar disorder patients.MethodsA total of 89 subjects, comprising 35 patients with bipolar disorder, 32 patients with schizophrenia, and 22 healthy controls were evaluated. The bipolar disorder cases comprised 10 depressed patients, 15 patients with mania, and 10 euthymic patients. The N1/P2 peak-to-peak amplitudes were measured at 5 stimulus intensities, and the LDAEP was calculated as the slope of the linear regression. Both cortical and source LDAEP values were calculated.ResultsLDAEP varied according to mood statuses, and was significantly stronger in cases of euthymia, depression, and mania. Cortical LDAEP was significantly stronger in patients with bipolar euthymia compared with schizophrenia, stronger in bipolar depression than in schizophrenia, stronger in healthy controls than in schizophrenia patients, and stronger in healthy controls than in patients with bipolar mania. Source LDAEP was significantly stronger in patients with bipolar euthymia, bipolar depression, and bipolar mania compared with schizophrenia, stronger in bipolar euthymia than in bipolar mania. Psychotic features weakened the source LDAEP relative to nonpsychotic features. The severity of the depressive symptom was negatively correlated with source LDAEP.ConclusionThese findings suggest that the serotonin activity of patients with bipolar disorder may vary according to mood status. A longitudinal follow-up study should be pursued using drug-naive subjects.

Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants

The loudness dependence of the auditory evoked potential (LDAEP) has been reported to be an effective non-invasive measure of central serotonergic neurotransmission. However, acute manipulations of the serotonergic system in humans and animals have yielded inconsistent findings. In this study, we examined the chronic effect of serotonergic manipulation using the selective serotonin reuptake inhibitor, sertraline, on the LDAEP. In addition, we examined the influence of 5-HTTLPR genotype and individual differences in plasma drug concentrations on the LDAEP. The study utilised a double-blind, placebo-controlled, between-group design in which 40 (24 female) healthy adults (M age = 22.0 years, SE = 0.7) were tested following placebo or sertraline for an average of 24 days. The LDAEP was assessed 6 h post-final dose, and changes in the slope of amplitude of the N1/P2 across intensities (60, 70, 80, 90, 100 dB) were examined at Cz. The sertraline group had a significantly smaller LDAEP than the placebo group [F(1,38) = 5.97, p = 0.02]. Drug plasma levels did not correlate with the LDAEP in the sertraline group, and there was no influence of 5-HTTLPR genotype. We show for the first time that chronically modulating serotonin neurotransmission alters the LDAEP in healthy adults, consistent with extant literature indicating a moderating role of serotonin on this neurophysiological biomarker. The findings from this study together with previous studies suggest that the LDAEP may be a more sensitive marker of long-term or chronic rather than acute changes in the serotonin system.

Evidence for sex differences in the loudness dependence of the auditory evoked potential in humans

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a marker of the serotonin system, although studies directly examining the relationship between acute changes in serotonin and the LDAEP have been inconsistent. Given the reported sex dichotomy in serotonin neurotransmission, this study examined if there are sex differences in the LDAEP. Data from 65 healthy participants from four independent studies were pooled, and their N1/P2 slopes were quantified. Mean N1/P2 slopes for female participants were higher than those for male participants (p < 0.0001). These findings suggest that the LDAEP is modulated by sex potentially because of differences in serotonergic neurotransmission, and these differences may account for some of the inconsistent findings linking serotonin function and LDAEP.

The loudness dependence of the auditory evoked potential (LDAEP) as a predictor of the response to escitalopram in patients with generalized anxiety disorder

The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a potential biological marker of central serotonergic activity. This study aimed to test the hypothesis that the LDAEP can be used to predict the response to escitalopram in patients with GAD. Twenty-five patients with GAD were recruited. Scores on the Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression-Severity Scale (CGI-S), and Beck Anxiety Inventory (BAI) were evaluated. To evaluate the LDAEP, the auditory event-related potential was measured before beginning medication. Peak-to-peak N1/P2 amplitudes and current source densities were calculated at five stimulus intensities, and the LDAEP was calculated as the linear-regression slope. The current source densities of the evoked potentials were analyzed by standardized low-resolution brain electromagnetic tomography (sLORETA). The loudness dependence of the current densities (sLORETA-LDAEP) was also calculated. The pretreatment LDAEPs of all patients were positively correlated with the CGI-S response rates at 4 and 8 weeks, and with the HAM-A and BAI response rates at 8 weeks. The sLORETA-LDAEPs were positively correlated with the HAM-A response rates after 8 weeks of treatment. The HAM-A and CGI response rates at 8 weeks were higher in patients with a strong pretreatment LDAEP than in those with a weak LDAEP. The present study revealed that GAD patients with a favorable response to escitalopram treatment are characterized by a stronger pretreatment LDAEP. Measurement of the LDAEP appears to provide useful clinical information for predicting treatment responses in patients with GAD.

The loudness dependence auditory evoked potential is insensitive to acute changes in serotonergic and noradrenergic neurotransmission

The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as an electrophysiological marker for assessing serotonergic function in vivo in humans, although accumulating evidence suggests that it is insensitive to acute changes in serotonergic neurotransmission. Very little is known about the sensitivity of the LDAEP to other neurotransmitter systems including the noradrenergic system. The current study examined the effects of noradrenergic modulation as well as serotonergic modulation on the LDAEP. The study utilised a double-blind placebo-controlled design in which the LDAEP in 17 healthy males and females was tested following acute administration of each of citalopram (20 mg), reboxetine (4 mg) and placebo. Neither citalopram nor reboxetine modulated the LDAEP relative to placebo treatment (p > 0.05). These findings suggest that the LDAEP is insensitive to acute changes in serotonergic or noradrenergic neurotransmission and thus is a poor pharmacodynamic marker of these systems.

Interaction of estrogen with central serotonergic mechanisms in human sensory processing: loudness dependence of the auditory evoked potential and mismatch negativity

Estrogen may be involved in schizophrenia by inhibiting serotonin-1A (5-HT(1A)) receptor function. We examined the effects of estrogen pre-treatment on modulation of loudness dependence of the auditory evoked potential (LDAEP) and mismatch negativity by the 5-HT(1A) receptor partial agonist, buspirone. Using a double-blind, placebo-controlled, repeated-measures design in healthy female volunteers, we observed that buspirone treatment significantly increased LDAEP slope. Estrogen increased LDAEP slope on its own, and a further LDAEP increase by buspirone was not seen after estrogen pre-treatment. Similar results were observed for mismatch negativity, where buspirone caused a small increase of latency, although not amplitude, after placebo but not estrogen pre-treatment, which enhanced mismatch negativity latency on its own. These results are in line with our previous findings on prepulse inhibition showing an inhibitory effect of estrogen on the action of buspirone. Taken together, these data suggest that estrogen may inhibit 5-HT(1A) receptor-mediated disruptions of auditory processing.

The loudness dependence of the auditory evoked potential (LDAEP) in schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, and healthy controls

Background Serotonergic dysfunction in schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, and healthy controls was evaluated by measuring the activity of the loudness dependence of the auditory evoked potential (LDAEP). Methods The 357 subjects who were evaluated comprised 55 normal controls, 123 patients with major depressive disorder, 37 with bipolar disorder, 46 with schizophrenia, 37 with panic disorder (PD), 31 with generalized anxiety disorder (GAD), and 28 with post-traumatic stress disorder (PTSD). Results LDAEP was significantly stronger in healthy controls than in patients with either bipolar disorder ( p = 0.025) or schizophrenia ( p = 0.008), and significantly stronger in patients with major depressive disorder than in those with bipolar disorder ( p = 0.01) or schizophrenia ( p = 0.03). LDAEP did not differ significantly between patients with major depressive disorder and healthy control subjects ( p = 0.667), or between healthy control subjects and patients with anxiety disorder, including PD ( p = 0.469), GAD ( p = 0.664), and PTSD ( p = 0.167). Conclusion The findings of the present study reveal that patients with major psychiatric disorders exhibit different strengths of LDAEP according to their serotonin-related pathology. Studies controlled for psychotropic medication, menstruation cycle, and smoking are needed.

The loudness dependence of the auditory evoked potential (LDAEP) as an in vivo biomarker of central serotonergic function in humans: rationale, evaluation and review of findings

The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a valid means of non-invasively assessing in vivo central serotonin (5-hydroxytryptamine, 5-HT) function in humans. The specificity and sensitivity of the LDAEP to changes in 5-HT neurotransmission have recently been explored directly in a number of pharmacological and genetic studies. Subsequently, this review was undertaken in an attempt to critically evaluate the potential role of the LDAEP as a marker of the central 5-HT function. Findings from clinical, experimental animal and human studies examining the relationship between the LDAEP and the 5-HT system as well as other neurochemical systems including dopaminergic, glutamatergic and the cholinergic systems were reviewed. The majority of evidence for an association between the LDAEP and 5-HT has come from animal studies. Indirect studies in clinical disorders of presumed serotonergic dysfunction have been circumstantial and inconsistent with more recent investigations utilising direct genetic association studies also providing conflicting reports. Pharmacological studies in humans provide overwhelming evidence that the LDAEP is insensitive to acute changes in 5-HT function, with additional evidence outlining sensitivity to other neurotransmitter systems including the glutamatergic system. The available evidence suggests that the LDAEP lacks sensitivity and specificity to acute changes in serotonergic neurotransmission. Overall the findings do not provide strong support for its utility as a marker of central 5-HT function. However the LDAEP shows more promise as a potential predictor of antidepressant treatment response and this predictive ability may provide the basis for future research involving the LDAEP.

Effects of selective and combined serotonin and dopamine depletion on the loudness dependence of the auditory evoked potential (LDAEP) in humans

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a possible in vivo measure of central serotonin function. However, more recent studies suggest that the LDAEP may be modulated by multiple neuromodulatory systems in addition to the serotonergic system. Accordingly we further examined the effects of selective serotonin, dopamine and simultaneous serotonin and dopamine depletion on the LDAEP in healthy subjects. The study employed a placebo-controlled, double-blind, cross over design. Fourteen subjects were tested under four acute treatment conditions: placebo (balanced amino acid drink), tryptophan (serotonin) depletion (ATD), tyrosine/phenylalanine (dopamine) depletion (ATPD) and combined tryptophan/tyrosine/phenylalanine (serotonin and dopamine) depletion (CMD). Testing was conducted 5.5 h post-depletion and changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at C(Z). Greater than 80% plasma precursor depletion was achieved across all conditions. Despite significant depletion of monoamine precursors, ATD, (p = 0.318), ATPD (p = 0.061) and CMD (p = 0.104) had no effects on the LDAEP (60-100 dB). Acute serotonin and dopamine depletion did not modulate the LDAEP. This finding adds support to growing evidence that the LDAEP is insensitive to acute changes in serotonin and dopamine neurotransmission.

An examination of acute changes in serotonergic neurotransmission using the loudness dependence measure of auditory cortex evoked activity: effects of citalopram, escitalopram and sertraline

The underlying effect of serotonergic neurotransmission has been implicated in several psychiatric disorders. The inability to routinely and non-invasively determine the integrity of the serotonergic system in vivo has limited our understanding of disorders with a putative serotonergic abnormality. The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a reliable measure of central serotonin function in humans. While animal studies suggest that the LDAEP is sensitive to changes in central serotonin neurotransmission, evidence in humans has been indirect and inconsistent. The aim of this study was to assess the sensitivity of the LDAEP to acute augmentation in central serotonergic neurotransmission in humans. The study used a double-blind, placebo-controlled cross-over design, in which healthy subjects were tested under four acute treatment conditions, with pharmacologically equivalent single doses of placebo, escitalopram (10 mg), citalopram (20 mg) and sertraline (50 mg) to examine the direct effect of acute enhancement of synaptic serotonin on the LDAEP. Furthermore, the outcome of the serotonergic modulatory effects on the LDAEP was also examined using two methods (dipole source analysis (DSA) vs. scalp analysis). Escitalopram, citalopram and sertraline had no effects on the LDAEP and were independent of the analysis method used. These findings question the sensitivity of the LDAEP to acute changes in serotonin neurotransmission and its validity as a reliable measure of central serotonin function in humans.

High-dose glycine inhibits the loudness dependence of the auditory evoked potential (LDAEP) in healthy humans

The loudness dependence of the auditory evoked Potential (LDAEP) has been suggested to be a putative marker of central serotonin function, with reported abnormalities in clinical disorders presumed to reflect serotonin dysfunction. Despite considerable research, very little is known about the LDAEP's sensitivity to other neurotransmitter systems. Given the role of N-methyl-D-aspartate (NMDA) receptors in modulating pyramidal cell activity in cortico-cortico and thalamo-cortical loops, we examined the effect of targeting the glycine modulatory site of the NMDA receptor with high-dose glycine on the LDAEP in healthy subjects. The study was a double-blind, placebo-controlled repeated-measures design in which 14 healthy participants were tested under two acute treatment conditions, placebo and oral glycine (0.8 g/kg). Changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at C(Z). Compared to placebo, high-dose glycine induced a weaker LDAEP (a pronounced decrease in the slope of the N1/P2 with increasing tone loudness; p < 0.02). While the exact mechanism responsible for the effects of glycine on the LDAEP are not known, the findings suggest an inhibitory effect in the cortex, possibly via activation of NMDA receptors on GABA interneurons or inhibitory glycine receptors. The findings add to the growing literature exhibiting modulation of the LDAEP by multiple neurochemical systems in addition to the serotonergic system.

Prediction of treatment response in major depression: Integration of concepts

Background Two promising approaches have been introduced for the prediction of treatment response in major depression: one concept is based on the activity in the rostral anterior cingulate cortex (rACC). Subjects with higher metabolic rates respond better to sleep deprivation or antidepressive medication. Another approach is the investigation of the loudness dependence of the auditory evoked potential (LDAEP). Here, a high LDAEP is supposed to reflect low central serotonergic activity. We present the first study comparing both approaches in the same group of patients. Methods Patients with major depression ( n = 20) were investigated using both resting EEG and LDAEP before treatment with either citalopram or reboxetine. Results We found significant differences between responders and non-responders in the rACC in the theta-frequency range (6.5–8 Hz, p < 0.05). In the subgroup of patients, treated with citalopram we found higher LDAEP-values in responders versus non-responders ( p < 0.05) and a significant correlation between pre-treatment-LDAEP and improvement in the Hamilton score after treatment ( r = 0.71, p < 0.05). Conclusions In combining both methods a prediction whether a patient with major depression might be at risk for non-response to a standard therapy as well as a suggestion for a pharmacological approach of choice seems to be possible.

Dopamine receptor stimulation does not modulate the loudness dependence of the auditory evoked potential in humans

The Loudness Dependence of the Auditory Evoked Potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans; however, its specificity for the serotonin system remains a topic of debate, with possible modulation of this purported serotonin marker by other neurotransmitters, including dopamine. We examined the effect of dopaminergic modulation on the LDAEP using the D1/D2/D3 dopamine receptor agonist pergolide and the D2/D3 agonist bromocriptine. The study was a double-blind, placebo-controlled repeated-measures design in which healthy participants were tested under three acute treatment conditions: placebo, bromocriptine (2.5 mg), and pergolide (0.1 mg). Changes in the amplitude of the N1/P2 at intensities (60, 70, 80, 90, and 100 dB) were examined at C Z. Acute stimulation of D1/D2/D3 receptors with pergolide and D2/D3 receptors with bromocriptine in comparison with placebo had no effect on the LDAEP. These findings indicate that acute stimulation of dopamine D1, D2, and D3 receptors does not modulate the LDAEP in humans. Although the findings suggest that the LDAEP may not be modulated by acute changes in dopamine neurotransmission, further studies are needed to fully characterize its dopaminergic sensitivity.

Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans. The most convincing evidence for a direct relationship between serotonergic function and LDAEP to date has come from animal studies, while evidence in humans has been circumstantial and inconsistent. In the current study, we examine the direct effect of serotonergic modulation with the selective serotonin reuptake inhibitor (SSRI) citalopram on the LDAEP. The study was a double-blind placebo controlled design in which healthy participants were tested under two acute treatment conditions: placebo and citalopram (20 mg). Enhancement of serotonin function with citalopram in comparison to placebo decreased the slope of the LDAEP (i.e. weaker LDAEP). The findings provide direct evidence in humans, of a relationship between central serotonin function and the LDAEP, supporting findings previously observed in animals and clinical populations. Together the results provide further support for the validity of the LDAEP as a non-invasive in vivo measure of central serotonin function in humans.