Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). METHODS: The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. ETHICS AND DISSEMINATION: The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.

How neurotypical listeners recognize emotions expressed through vocal cues by speakers with high-functioning autism.

We conducted an investigation to explore how neurotypical (NT) listeners perceive the emotional tone of voice in sentences spoken by individuals with high-functioning autism spectrum disorders (ASD) and NT speakers. The investigation included both male and female speakers from both groups. In Study 1, NT listeners were asked to identify the emotional prosody (anger, fear, happiness, surprise or neutral) conveyed by the speakers. Results revealed that emotional expressions produced by male ASD speakers were generally less accurately recognized compared to male NT speakers. In contrast, emotions expressed by female ASD speakers were more accurately categorized compared to female NT speakers, except when expressing fear. This suggests that female ASD speakers may not express emotional prosody in the same way as their male counterparts. In Study 2, a subset of produced materials was rated for valence, voice modulation, and voice control to supplement Study 1 results: Female ASD speakers sounded less negative when expressing fear compared to female NT speakers. Male ASD speakers were perceived as less positive than NT speakers when expressing happiness. Voice modulation also differed between groups, showing a tendency for ASD speakers to follow different display rules for both positive emotions (happiness and surprise) tested. Finally, male ASD speakers were rated to use voice cues less appropriately compared to NT male speakers, an effect less pronounced for female ASD speakers. Together, the results imply that difficulties in social interactions among individuals with high-functioning ASD could be due to non-prototypical voice use of male ASD speakers and emphasize that female individuals do not show the same effects.

The brain in motion-cognitive effects of simultaneous motor activity.

During the last 30 years, a large number of behavioral studies have investigated the effect of simultaneous exercise on cognitive functions. The heterogeneity of the results has been attributed to different parameters, such as intensity or modality of physical activity, and the investigated cognitive processes. More recent methodological improvements have enabled to record electroencephalography (EEG) during physical exercise. EEG studies combining cognitive tasks with exercise have described predominantly detrimental effects on cognitive processes and EEG parameters. However, differences in the underlying rationale and the design of EEG versus behavioral studies make direct comparisons between both types of studies difficult. In this narrative review of dual-task experiments we evaluated behavioral and EEG studies and discuss possible explanations for the heterogeneity of results and for the discrepancy between behavioral and EEG studies. Furthermore, we provide a proposal for future EEG studies on simultaneous motion to be a useful complement to behavioral studies. A crucial factor might be to find for each cognitive function the motor activity that matches this function in terms of attentional focus. This hypothesis should be investigated systematically in future studies.

Pre-stimulus beta power varies as a function of auditory-motor synchronization and temporal predictability.

Introduction: Auditory-motor interactions can support the preparation for expected sensory input. We investigated the periodic modulation of beta activity in the electroencephalogram to assess the role of active auditory-motor synchronization. Pre-stimulus beta activity (13-30 Hz) has been interpreted as a neural signature of the preparation for expected sensory input. Methods: In the current study, participants silently counted frequency deviants in sequences of pure tones either during a physically inactive control condition or while pedaling on a cycling ergometer. Tones were presented either rhythmically (at 1 Hz) or arrhythmically with variable intervals. In addition to the pedaling conditions with rhythmic (auditory-motor synchronization, AMS) or arrhythmic stimulation, a self-generated stimulus condition was used in which tones were presented in sync with the participants' spontaneous pedaling. This condition served to explore whether sensory predictions are driven primarily by the auditory or by the motor system. Results: Pre-stimulus beta power increased for rhythmic compared to arrhythmic stimulus presentation in both sitting and pedaling conditions but was strongest in the AMS condition. Furthermore, beta power in the AMS condition correlated with motor performance, i.e., the better participants synchronized with the rhythmic stimulus sequence, the higher was pre-stimulus beta power. Additionally, beta power was increased for the self-generated stimulus condition compared with arrhythmic pedaling, but there was no difference between the self-generated and the AMS condition. Discussion: The current data pattern indicates that pre-stimulus beta power is not limited to neuronal entrainment (i.e., periodic stimulus presentation) but represents a more general correlate of temporal anticipation. Its association with the precision of AMS supports the role of active behavior for auditory predictions.

Auditory-motor coupling affects phonetic encoding.

Recent studies have shown that moving in synchrony with auditory stimuli boosts attention allocation and verbal learning. Furthermore rhythmic tones are processed more efficiently than temporally random tones ('timing effect'), and this effect is increased when participants actively synchronize their motor performance with the rhythm of the tones, resulting in auditory-motor synchronization. Here, we investigated whether this applies also to sequences of linguistic stimuli (syllables). We compared temporally irregular syllable sequences with two temporally regular conditions where either the interval between syllable onsets (stimulus onset asynchrony, SOA) or the interval between the syllables' vowel onsets was kept constant. Entrainment to the stimulus presentation frequency (1 Hz) and event-related potentials were assessed in 24 adults who were instructed to detect pre-defined deviant syllables while they either pedaled or sat still on a stationary exercise bike. We found larger 1 Hz entrainment and P300 amplitudes for the SOA presentation during motor activity. Furthermore, the magnitude of the P300 component correlated with the motor variability in the SOA condition and 1 Hz entrainment, while in turn 1 Hz entrainment correlated with auditory-motor synchronization performance. These findings demonstrate that acute auditory-motor coupling facilitates phonetic encoding.

Cognitive effects of rhythmic auditory stimulation in Parkinson's disease: A P300 study.

Rhythmic auditory stimulation (RAS) may compensate dysfunctions of the basal ganglia (BG), involved with intrinsic evaluation of temporal intervals and action initiation or continuation. In the cognitive domain, RAS containing periodically presented tones facilitates young healthy participants' attention allocation to anticipated time points, indicated by better performance and larger P300 amplitudes to periodic compared to random stimuli. Additionally, active auditory-motor synchronization (AMS) leads to a more precise temporal encoding of stimuli via embodied timing encoding than stimulus presentation adapted to the participants' actual movements. Here we investigated the effect of RAS and AMS in Parkinson's disease (PD). 23 PD patients and 23 healthy age-matched controls underwent an auditory oddball task. We manipulated the timing (periodic/random/adaptive) and setting (pedaling/sitting still) of stimulation. While patients elicited a general timing effect, i.e., larger P300 amplitudes for periodic versus random tones for both, sitting and pedaling conditions, controls showed a timing effect only for the sitting but not for the pedaling condition. However, a correlation between P300 amplitudes and motor variability in the periodic pedaling condition was obtained in control participants only. We conclude that RAS facilitates attentional processing of temporally predictable external events in PD patients as well as healthy controls, but embodied timing encoding via body movement does not affect stimulus processing due to BG impairment in patients. Moreover, even with intact embodied timing encoding, such as healthy elderly, the effect of AMS depends on the degree of movement synchronization performance, which is very low in the current study.

Stability of BDNF in Human Samples Stored Up to 6 Months and Correlations of Serum and EDTA-Plasma Concentrations.

Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at -80 °C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA)-plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter-assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to rs = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations.

Synchronised vestibular signals increase the P300 event-related potential elicited by auditory oddballs.

The perception of beat within an auditory rhythm can be facilitated when accompanied by synchronised movements. Electrophysiological investigation shows that this facilitatory effect is associated with a larger P300 amplitude. It has remained unclear, however, which movement-related processes drive this P300 effect. To investigate whether vestibular signals play a role, we administered alternating, sub-sensory (mean=.3mA) galvanic current to the vestibular nerves of participants while they counted the number of oddballs presented in a stream of tones played at a rate of 1Hz. Consistent with a vestibular effect, the P300 elicited by the oddballs was increased during stimulation relative to a sham condition, but only when the frequency of the alternating current matched that at which the tones were played. This finding supports the general idea that the vestibular system is involved in audio-motor synchronisation and is the first to show by electrophysiological means that it influences cognitive processes involved in beat perception.

The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults.

In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans.

Actively but not passively synchronized motor activity amplifies predictive timing.

Previous studies have shown that the effect of temporal predictability of presented stimuli on attention allocation is enhanced by auditory-motor synchronization (AMS). The present P300 event-related potential study (N=20) investigated whether this enhancement depends on the process of actively synchronizing one's motor output with the acoustic input or whether a passive state of auditory-motor synchrony elicits the same effect. Participants silently counted frequency deviants in sequences of pure tones either during a physically inactive control condition or while pedaling on a cycling ergometer. Tones were presented either at fixed or variable intervals. In addition to the pedaling conditions with fixed or variable stimulation, there was a third condition in which stimuli were adaptively presented in sync with the participants' spontaneous pedaling. We replicated the P300 enhancement for fixed versus variable stimulation and the amplification of this effect by AMS. Synchronization performance correlated positively with P300 amplitude in the fixed stimulation condition. Most interestingly, P300 amplitude was significantly reduced for the passive synchronization condition by adaptive stimulus presentation as compared to the fixed stimulation condition. For the first time we thus provide evidence that it is not the passive state of (even perfect) auditory-motor synchrony that facilitates attention allocation during AMS but rather the active process of synchronizing one's movements with external stimuli.

Basal ganglia contribution to rule expectancy and temporal predictability in speech.

The current work set out to answer three questions: (1) Are reported syntactic deficits in patients with structural damage to the basal ganglia (BG) in the cortico-striato-thalamo-cortical systems (CSTCS) the result of a syntax specific computational deficit or are they potentially a consequence of a generalized timing deficit? (2) Do BG patients suffer from a simple beat perception deficit in speech comparable to the one reported in music? (3) Can regular speech meter (i.e., a pattern of beats induced by the regular alteration of stressed and unstressed syllable accents) ameliorate the computation of syntactically marked information by making speech events temporally predictable and salient? The latter 'remediation' hypothesis would predict that when speech events (i.e., those that are syntactically marked) are metrically aligned to the syllabic accent structure, the computation of syntactic information is facilitated or in the case of patients ameliorated. During continuous EEG measurement nineteen patients with focal BG lesions and matched healthy controls listened to metrically regular and syntactically well-formed sentences and metrically well-formed sentences that either violated syntactic expectancy, metrical expectancy, or both. While healthy controls showed an expected P600 response in the event-related brain potential (ERP) to all expectancy violations, BG patients showed overall comparable P600 responses to all, but the metrical expectancy violation. These results confirm that (1) BG patients suffer from a simple beat perception deficit in speech and (2) regular speech meter ameliorates the computation of syntactically marked information in the speech signal. We propose that a domain general sensorimotor cerebello-thalamo-cortical system (CTCS), involved in event-based temporal processing, engages in the remediation of dysfunctional cortico-striato-thalamo-cortical timing that affects the timely computation of linguistic (i.e., syntax) information in the speech signal.

Treadmill walking during vocabulary encoding improves verbal long-term memory.

Moderate physical activity improves various cognitive functions, particularly when it is applied simultaneously to the cognitive task. In two psychoneuroendocrinological within-subject experiments, we investigated whether very low-intensity motor activity, i.e. walking, during foreign-language vocabulary encoding improves subsequent recall compared to encoding during physical rest. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum and salivary cortisol. Previous research has associated both substances with memory performance.In both experiments, subjects performed better when they were motorically active during encoding compared to being sedentary. BDNF in serum was unrelated to memory performance. In contrast we found a positive correlation between salivary cortisol concentration and the number of correctly recalled items. In summary, even very light physical activity during encoding is beneficial for subsequent recall.

Enhanced musical rhythmic perception in Turkish early and late learners of German.

As language rhythm relies partly on general acoustic properties, such as intensity and duration, mastering two languages with distinct rhythmic properties (i.e., stress position) may enhance musical rhythm perception. We investigated whether competence in a second language (L2) with different rhythmic properties than a L1 affects musical rhythm aptitude. Turkish early (TELG) and late learners (TLLG) of German were compared to German late L2 learners of English (GLE) regarding their musical rhythmic aptitude. While Turkish and German present distinct linguistic rhythm and metric properties, German and English are rather similar in this regard. To account for inter-individual differences, we measured participants' short-term and working memory (WM) capacity, melodic aptitude, and time they spent listening to music. Both groups of Turkish L2 learners of German perceived rhythmic variations significantly better than German L2 learners of English. No differences were found between early and late learners' performance. Our findings suggest that mastering two languages with different rhythmic properties enhances musical rhythm perception, providing further evidence of shared cognitive resources between language and music.

Auditory-motor synchronization facilitates attention allocation.

Temporal predictability of auditory events induces larger P300 amplitudes and shorter P300 latencies compared to stimulus presentation with variable onset asynchronies. This suggests that periodic stimuli lead to neuronal entrainment resulting in a more efficient allocation of attentional resources. Simultaneous synchronized motor activity should facilitate the precise temporal encoding of acoustic sequences. Therefore the current event-related potential study investigated whether embodied stimulus encoding enhances the reported effects of stimulus periodicity. We found that simultaneous pedaling on an ergometer compared to a physically passive situation amplified the predictability effect on the P300 component. Furthermore, the temporal variability of cycling behavior correlated positively with both P300 latency and P300 amplitude. These findings indicate that auditory-motor synchronization enhances the attentional processing of periodical auditory stimuli.

Physical exercise during encoding improves vocabulary learning in young female adults: a neuroendocrinological study.

Acute physical activity has been repeatedly shown to improve various cognitive functions. However, there have been no investigations comparing the effects of exercise during verbal encoding versus exercise prior to encoding on long-term memory performance. In this current psychoneuroendocrinological study we aim to test whether light to moderate ergometric bicycling during vocabulary encoding enhances subsequent recall compared to encoding during physical rest and encoding after being physically active. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum which has been previously shown to correlate with learning performance. We also controlled for the BDNF val66met polymorphism. We found better vocabulary test performance for subjects that were physically active during the encoding phase compared to sedentary subjects. Post-hoc tests revealed that this effect was particularly present in initially low performers. BDNF in serum and BDNF genotype failed to account for the current result. Our data indicates that light to moderate simultaneous physical activity during encoding, but not prior to encoding, is beneficial for subsequent recall of new items.

Speech rhythm facilitates syntactic ambiguity resolution: ERP evidence.

In the current event-related potential (ERP) study, we investigated how speech rhythm impacts speech segmentation and facilitates the resolution of syntactic ambiguities in auditory sentence processing. Participants listened to syntactically ambiguous German subject- and object-first sentences that were spoken with either regular or irregular speech rhythm. Rhythmicity was established by a constant metric pattern of three unstressed syllables between two stressed ones that created rhythmic groups of constant size. Accuracy rates in a comprehension task revealed that participants understood rhythmically regular sentences better than rhythmically irregular ones. Furthermore, the mean amplitude of the P600 component was reduced in response to object-first sentences only when embedded in rhythmically regular but not rhythmically irregular context. This P600 reduction indicates facilitated processing of sentence structure possibly due to a decrease in processing costs for the less-preferred structure (object-first). Our data suggest an early and continuous use of rhythm by the syntactic parser and support language processing models assuming an interactive and incremental use of linguistic information during language processing.

Aesthetic and emotional effects of meter and rhyme in poetry.

Metrical patterning and rhyme are frequently employed in poetry but also in infant-directed speech, play, rites, and festive events. Drawing on four line-stanzas from nineteenth and twentieth German poetry that feature end rhyme and regular meter, the present study tested the hypothesis that meter and rhyme have an impact on aesthetic liking, emotional involvement, and affective valence attributions. Hypotheses that postulate such effects have been advocated ever since ancient rhetoric and poetics, yet they have barely been empirically tested. More recently, in the field of cognitive poetics, these traditional assumptions have been readopted into a general cognitive framework. In the present experiment, we tested the influence of meter and rhyme as well as their interaction with lexicality in the aesthetic and emotional perception of poetry. Participants listened to stanzas that were systematically modified with regard to meter and rhyme and rated them. Both rhyme and regular meter led to enhanced aesthetic appreciation, higher intensity in processing, and more positively perceived and felt emotions, with the latter finding being mediated by lexicality. Together these findings clearly show that both features significantly contribute to the aesthetic and emotional perception of poetry and thus confirm assumptions about their impact put forward by cognitive poetics. The present results are explained within the theoretical framework of cognitive fluency, which links structural features of poetry with aesthetic and emotional appraisal.

P3b reflects periodicity in linguistic sequences.

Temporal predictability is thought to affect stimulus processing by facilitating the allocation of attentional resources. Recent studies have shown that periodicity of a tonal sequence results in a decreased peak latency and a larger amplitude of the P3b compared with temporally random, i.e., aperiodic sequences. We investigated whether this applies also to sequences of linguistic stimuli (syllables), although speech is usually aperiodic. We compared aperiodic syllable sequences with two temporally regular conditions. In one condition, the interval between syllable onset was fixed, whereas in a second condition the interval between the syllables' perceptual center (p-center) was kept constant. Event-related potentials were assessed in 30 adults who were instructed to detect irregularities in the stimulus sequences. We found larger P3b amplitudes for both temporally predictable conditions as compared to the aperiodic condition and a shorter P3b latency in the p-center condition than in both other conditions. These findings demonstrate that even in acoustically more complex sequences such as syllable streams, temporal predictability facilitates the processing of deviant stimuli. Furthermore, we provide first electrophysiological evidence for the relevance of the p-center concept in linguistic stimulus processing.

Kinetics of serum brain-derived neurotrophic factor following low-intensity versus high-intensity exercise in men and women.

Physical activity has been shown to enhance circulating brain-derived neurotrophic factor (BDNF) in animals and humans. However, the exact time course and sex-specific modulation of peripheral BDNF in response to exercise are still poorly understood. We examined the kinetics of BDNF serum concentrations in response to perceived high-intensity and low-intensity exercise, and during a subsequent recovery period by taking several blood samples during each phase. Furthermore, we compared the BDNF concentration between young men and women taking oral contraceptives. We found transient BDNF elevations during physical activity only for the high-intensity condition. Here, BDNF reached its maximum serum concentration after 20 min of exercise, and returned to baseline after approximately 10 min of recovery. Although there were no sex differences during baseline or recovery, the increase in the BDNF concentration during the exercise phase was more pronounced in men than in women.