Neuroimaging and serum biomarkers of neurodegeneration and neuroplasticity in Parkinson's disease patients treated by intermittent theta-burst stimulation over the bilateral primary motor area: a randomized, double-blind, sham-controlled, crossover trial study.

Background and objectives: Intermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson's disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity. Methods: A total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS. Discussion: The findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.

Menstrual cycle and exogenous attention toward emotional expressions.

Several studies suggest that the menstrual cycle affects emotional processing. However, these results may be biased by including women with premenstrual syndrome (PMS) in the samples. PMS is characterized by negative emotional symptomatology, such as depression and/or anxiety, during the luteal phase. This study aimed to explore the modulation of exogenous attention to emotional facial expressions as a function of the menstrual cycle in women without PMS. For this purpose, 55 women were selected (from an original volunteer sample of 790) according to rigorous exclusion criteria. Happy, angry, and neutral faces were presented as distractors, while both behavioral performance in a perceptual task and event-related potentials (ERPs) were recorded. This task was applied during both phases of the menstrual cycle (luteal and follicular, counterbalanced), and premenstrual symptomatology was monitored daily. Traditional and Bayesian ANOVAs on behavioral data (reaction times and errors in the task) and ERP indices (P1, N170, N2, and LPP amplitudes) confirmed the expected lack of an interaction of phase and emotion. Taken together, these results indicate that women free of PMS present steady exogenous attention levels to emotionally positive and negative stimuli regardless of the menstrual phase.

Exogenous Attention to Emotional Stimuli Presenting Realistic (3D) Looming Motion.

Previous research shows that dynamic stimuli, on the one hand, and emotional stimuli, on the other, capture exogenous attention due to their biological relevance. Through neural (ERPs) and behavioral measures (reaction times and errors), the present study explored the combined effect of looming motion and emotional content on attentional capture. To this end, 3D-recreated static and dynamic animals assessed as emotional (positive or negative) or neutral were presented as distractors while 71 volunteers performed a line orientation task. We observed a two-phase effect: firstly (before 300 ms), early components of ERPs (P1p and N2po) showed enhanced exogenous attentional capture by looming positive distractors and static threatening animals. Thereafter, dynamic and static threatening distractors received enhanced endogenous attention as revealed by both late ERP activity (LPC) and behavioral (errors) responses. These effects are likely explained by both the emotional valence and the distance of the stimulus at each moment.

Realistic (3D) looming of emotional visual stimuli: Attentional effects at neural and behavioral levels.

Previous research shows that endogenous attention (the controlled selection of certain aspects of our environment) is enhanced toward emotional stimuli due to its biological relevance. Although looming affective stimuli such as threat seem even more critical for survival, little is known about their effect on endogenous attention. Here, we recorded neural (event-related potentials, ERPs) and behavioral responses (errors and reaction times) to explore the combined effect of emotion and looming motion. 3D-recreated static and moving animals assessed as emotionally positive, negative, and neutral, were presented to participants (n = 71), who performed an indirect categorization task (vertebrate vs. invertebrate). Behavioral results showed better task performance, as reflected by lower number of errors and reaction times, in response to threatening stimuli. Neural indices revealed significant early (P1p, 150 milliseconds), intermediate (P2p, 240), and late (LPP, 450) effects, the latter being more intensely associated with behavior, as revealed by regression analyses. In general, neural indexes of attention to both static and dynamic stimuli showed a positivity offset in early stages and a negativity bias in subsequent phases. However, and importantly, the progressive inclusion of negative stimuli in the attentional focus is produced earlier in the case of dynamic (at P2p latency) than in static versions (at LPP). These results point to an enhancement of attention, particularly in temporal terms, toward stimuli combining motion and biological significance.

Enhanced N170 to outgroup faces: Perceptual novelty or prejudice?

Habituation to ethnic ingroup members has been reported to be greater than to ethnic outgroup members. This pattern could be due to the lack of perceptive experience (familiarity) with outgroup facial morphs or, alternatively, to the prejudice held toward that outgroup. We explored this disjunctive in 71 participants, all Spanish, who were experimentally habituated to faces from their Ingroup and to faces from two unfamiliar outgroups, one for which there is low probability of prejudice in this population (Non-prejudiced Outgroup), and one for which the probability of prejudice is higher (Prejudiced Outgroup). We indexed habituation through event-related potentials, concretely as the differential amplitude of the face-sensitive N170 component from Initial to Final trials of each group. Afterward, participants completed several prejudice measures. N170 showed significant habituation to all faces, though it did not differ among groups. However, a regression analysis revealed that individual habituation to the Outgroup faces was inversely related to implicit prejudice scores. Importantly, N170 amplitudes were maximal for the Prejudiced Outgroup in both Initial and Final trials. We conclude that these effects are explained by the prejudice held toward a specific outgroup rather than perceptive experience.

Temporal dynamics of amygdala response to emotion- and action-relevance.

It has been proposed that the human amygdala may not only encode the emotional value of sensory events, but more generally mediate the appraisal of their relevance for the individual's goals, including relevance for action or task-based needs. However, emotional and non-emotional/action-relevance might drive amygdala activity through distinct neural signals, and the relative timing of both kinds of responses remains undetermined. Here, we recorded intracranial event-related potentials from nine amygdalae of patients undergoing epilepsy surgery, while they performed variants of a Go/NoGo task with faces and abstract shapes, where emotion- and action-relevance were orthogonally manipulated. Our results revealed early amygdala responses to emotion facial expressions starting ~ 130 ms after stimulus-onset. Importantly, the amygdala responded to action-relevance not only with face stimuli but also with abstract shapes (squares), and these relevance effects consistently occurred in later time-windows (starting ~ 220 ms) for both faces and squares. A similar dissociation was observed in gamma activity. Furthermore, whereas emotional responses habituated over time, the action-relevance effect increased during the course of the experiment, suggesting progressive learning based on the task needs. Our results support the hypothesis that the human amygdala mediates a broader relevance appraisal function, with the processing of emotion-relevance preceding temporally that of action-relevance.

Prejudice drives exogenous attention to outgroups.

Exogenous attention allows the automatic detection of relevant stimuli and the reorientation of our current focus of attention towards them. Faces from an ethnic outgroup tend to capture exogenous attention to a greater extent than faces from an ethnic ingroup. We explored whether prejudice toward the outgroup, rather than lack of familiarity, is driving this effect. Participants (N = 76) performed a digit categorization task while distractor faces were presented. Faces belonged to (i) a prejudiced outgroup, (ii) a non-prejudiced outgroup and (iii) their ingroup. Half of the faces were previously habituated in order to increase their familiarity. Reaction times, accuracy and event-related potentials (ERPs) were recorded to index exogenous attention to distractor faces. Additionally, different indexes of explicit and implicit prejudice were measured, the latter being significantly greater towards prejudiced outgroup. N170 amplitude was greater to prejudiced outgroup-regardless of their habituation status-than to both non-prejudiced outgroup and ingroup faces and was associated with implicit prejudice measures. No effects were observed at the behavioral level. Our results show that implicit prejudice, rather than familiarity, is under the observed attention-related N170 effects and that this ERP component may be more sensitive to prejudice than behavioral measures under certain circumstances.

Retinotopy of emotion: Perception of negatively valenced stimuli presented at different spatial locations as revealed by event-related potentials.

Scarce previous data on how the location where an emotional stimulus appears in the visual scene modulates its perception suggest that, for functional reasons, a perceptual advantage may exist, vertically, for stimuli presented at the lower visual field (LoVF) and, horizontally, for stimuli presented at the left visual field (LeVF). However, this issue has been explored through a limited number of spatial locations, usually in a single spatial dimension (e.g., horizontal) and invariant eccentricities. Event-related potentials (ERPs) were recorded from 39 participants perceiving brief neutral (wheels) and emotional stimuli (spiders) presented at 17 different locations, one foveal and 16 at different peripheral coordinates. As a secondary scope, we explored the role of the magnocellular (M) and the parvocellular (P) visual pathways by presenting an isoluminant/heterochromatic (P-biased) and a heteroluminant/isochromatic version (M-biased) of each stimulus. Emo > Neu effects were observed in PN1 (120 ms) for stimuli located at fovea, and in PN2 (215 ms) for stimuli located both at fovea and diverse peripheral regions. A factorial approach to these effects further revealed that: (a) emotional stimuli presented in the periphery are efficiently perceived, without evident decrease from para- to perifovea; (b) peripheral Emo > Neu effects are reflected 95 ms later than foveal Emo > Neu effects in ERPs; (c) LoVF is more involved than UVF in these effects; (d) our data fail to support the LeVF advantage previously reported, and (e) Emo > Neu effects were significant for both M and P stimuli.

Human amygdala response to unisensory and multisensory emotion input: No evidence for superadditivity from intracranial recordings.

The amygdala is crucially implicated in processing emotional information from various sensory modalities. However, there is dearth of knowledge concerning the integration and relative time-course of its responses across different channels, i.e., for auditory, visual, and audiovisual input. Functional neuroimaging data in humans point to a possible role of this region in the multimodal integration of emotional signals, but direct evidence for anatomical and temporal overlap of unisensory and multisensory-evoked responses in amygdala is still lacking. We recorded event-related potentials (ERPs) and oscillatory activity from 9 amygdalae using intracranial electroencephalography (iEEG) in patients prior to epilepsy surgery, and compared electrophysiological responses to fearful, happy, or neutral stimuli presented either in voices alone, faces alone, or voices and faces simultaneously delivered. Results showed differential amygdala responses to fearful stimuli, in comparison to neutral, reaching significance 100-200 ms post-onset for auditory, visual and audiovisual stimuli. At later latencies, ∼400 ms post-onset, amygdala response to audiovisual information was also amplified in comparison to auditory or visual stimuli alone. Importantly, however, we found no evidence for either super- or subadditivity effects in any of the bimodal responses. These results suggest, first, that emotion processing in amygdala occurs at globally similar early stages of perceptual processing for auditory, visual, and audiovisual inputs; second, that overall larger responses to multisensory information occur at later stages only; and third, that the underlying mechanisms of this multisensory gain may reflect a purely additive response to concomitant visual and auditory inputs. Our findings provide novel insights on emotion processing across the sensory pathways, and their convergence within the limbic system.

Neurophysiological evidence for early modulation of amygdala activity by emotional reappraisal.

How emotions unfold through time in the brain, and how fast they can be regulated by voluntary control, remain unresolved. Psychological accounts of emotion regulation posit cognitive reappraisal mechanisms may alter early emotion generative processes directly, whereas suppression impacts only later processing stages, after emotion has arisen. However, to date, there is no neurophysiological data concerning the precise latency of emotion regulation effects on the amygdala, a major emotion processing relay in the brain. Here we record amygdala activity from six patients undergoing surgery for pharmaco-resistant epilepsy during both reappraisal and suppression. We find that emotion reappraisal strategy, but not suppression, modulates early neural responses to emotional scenes during an extended period of time, starting 130 ms post-stimulus onset. Further, reappraisal produced earlier impact on amygdala responses to positive compared to negative scenes. Our results provide the first neurophysiological support for theoretical accounts of emotion regulation that postulate an early modulation of emotion generative processes by reappraisal.

Ultrafast Cortical Gain Adaptation in the Human Brain by Trial-To-Trial Changes of Associative Strength in Fear Learning.

In fear conditioning, more efficient sensory processing of a stimulus (the conditioned stimulus, CS) that has acquired motivational relevance by being paired with an aversive event (the unconditioned stimulus, US) has been associated with increased cortical gain in early sensory brain areas (Miskovic and Keil, 2012). Further, this sensory gain modulation related to short-term plasticity changes occurs independently of aware cognitive anticipation of the aversive US, pointing toward implicit learning mechanisms (Moratti and Keil, 2009). However, it is unknown how quickly the implicit learning of CS-US associations results in the adaptation of cortical gain. Here, using steady-state visually evoked fields derived from human Magnetoencephalography (MEG) recordings in two experiments (N = 33, 17 females and 16 males), we show that stimulus-driven neuromagnetic oscillatory activity increases and decreases quickly as a function of associative strength within three or four trials, as predicted by a computationally implemented Rescorla-Wagner model with the highest learning rate. These ultrafast cortical gain adaptations are restricted to early visual cortex using a delay fear conditioning procedure. Short interval (500 ms) trace conditioning resulted in the same ultrafast activity modulations by associative strength, but in a complex occipito-parieto-temporo-frontal network. Granger causal analysis revealed that reverberating top-down and bottom-up influences between anterior and posterior brain regions during trace conditioning characterized this network. Critically, in both delay and trace conditioning, ultrafast cortical gain modulations as a function of associative strength occurred independently of conscious US anticipation.SIGNIFICANCE STATEMENT In ever-changing environments, learned associations between a cue and an aversive consequence must change under new stimulus-consequence contingencies to be adaptive. What predicts potential dangers now might be meaningless in the next situation. Predictive cues are prioritized, as reflected by increased sensory cortex activity for these cues. However, this modulation also must adapt to altered stimulus-consequence contingencies. Here, we show that human visual cortex activity can be modulated quickly according to ultrafast contingency changes within a few learning trials. This finding extends to frontal brain regions when the cue and the aversive event are separated in time. Critically, this ultrafast updating process occurs orthogonally to aware aversive outcome anticipation and therefore relies on unconscious implicit learning mechanisms.

Conditioned inhibitory and excitatory gain modulations of visual cortex in fear conditioning: Effects of analysis strategies of magnetocortical responses.

In unpredictable environments, stimuli that predict potential danger or its absence can change rapidly. Therefore, it is highly adaptive to prioritize incoming sensory information flexibly as a function of prior experience. Previously, these changes have only been conceptualized as excitatory gain increases in sensory cortices for acquired fear-relevant stimuli during associative learning. However, formal descriptions of associative processes by Rescorla and Wagner predict both conditioned excitatory and inhibitory processes in response systems for fear and safety cues, respectively. Magnetocortical steady-state visual evoked fields (ssVEFs) have been shown to vary in amplitude as a function of associative strength. Therefore, we wondered why previous studies reporting ssVEF modulations by fear learning did not observe conditioned inhibition of ssVEF responses for the safety cue. Three analysis strategies were applied: (1) traditional analysis of ssVEF amplitude at occipital MEG sensors, (2) applying a general linear model (GLM) at each sensor, and (3) fitting the same GLM to cortically localized ssVEF responses. First, we replicated previous findings of increased ssVEFs for acquired fear-relevant stimuli using all three analysis strategies. Critically, we demonstrated conditioned inhibition of ssVEF responses for fear-irrelevant cues for specific gradiometer sensor types using the traditional analysis technique and for all sensor types when applying a GLM to the sensor space. However, sensor space effects were rather small. In stark contrast, cortical source space effect sizes were most pronounced. The results of opposing CS+ and CS- modulations in sensory cortex reflect predictions of the Rescorla-Wagner model and current neurobiological findings.

A fast pathway for fear in human amygdala.

A fast, subcortical pathway to the amygdala is thought to have evolved to enable rapid detection of threat. This pathway's existence is fundamental for understanding nonconscious emotional responses, but has been challenged as a result of a lack of evidence for short-latency fear-related responses in primate amygdala, including humans. We recorded human intracranial electrophysiological data and found fast amygdala responses, beginning 74-ms post-stimulus onset, to fearful, but not neutral or happy, facial expressions. These responses had considerably shorter latency than fear responses that we observed in visual cortex. Notably, fast amygdala responses were limited to low spatial frequency components of fearful faces, as predicted by magnocellular inputs to amygdala. Furthermore, fast amygdala responses were not evoked by photographs of arousing scenes, which is indicative of selective early reactivity to socially relevant visual information conveyed by fearful faces. These data therefore support the existence of a phylogenetically old subcortical pathway providing fast, but coarse, threat-related signals to human amygdala.

Priming effects on the N400 in the affective priming paradigm with facial expressions of emotion.

We studied the effect of facial expression primes on the evaluation of target words through a variant of the affective priming paradigm. In order to make the affective valence of the faces irrelevant to the task, the participants were assigned a double prime-target task in which they were unpredictably asked either to identify the gender of the face or to evaluate whether the word was pleasant or unpleasant. Behavioral and electrophysiological (event-related potential, or ERP) indices of affective priming were analyzed. Temporal and spatial versions of principal components analyses were used to detect and quantify those ERP components associated with affective priming. Although no significant behavioral priming was observed, electrophysiological indices showed a reverse priming effect, in the sense that the amplitude of the N400 was higher in response to congruent than to incongruent negative words. Moreover, a late positive potential (LPP), peaking around 700 ms, was sensitive to affective valence but not to prime-target congruency. This pattern of results is consistent with previous accounts of ERP effects in the affective priming paradigm that have linked the LPP with evaluative priming and the N400 with semantic priming. Our proposed explanation of the N400 priming effects obtained in the present study is based on two assumptions: a double check of affective stimuli in terms of valence and specific emotion content, and the differential specificities of facial expressions of positive and negative emotions.

High arousal words influence subsequent processing of neutral information: evidence from event-related potentials.

Recent data suggest that word valence modulates subsequent cognitive processing. However, the contribution of word arousal is less understood. In this study, behavioral and electrophysiological measures to neutral nouns and pseudowords that were preceded by either a high-arousal or a low-arousal word were recorded during a lexical decision task. Effects were found at an electrophysiological level. Target words and pseudowords elicited enhanced N100 amplitudes when they were preceded by high- compared to low-arousing words. This effect may reflect perceptual potentiation during the allocation of attentional resources when the new stimulus is processed. Enhanced amplitudes in a late positivity when target words and pseudowords followed high-arousal primes were also observed, which could be related to sustained attention during supplementary analyses at a post-lexical level.

Early effects of emotion on word immediate repetition priming: electrophysiological and source localization evidence.

The processing of a stimulus benefits from the previous exposure of an identical stimulus, which is known as immediate repetition priming (IRP). Although several experimental manipulations modulate the size of this effect, the influence of affective information is still unclear. In order to explore the temporo-spatial characteristics of the interaction between emotion and IRP, event-related potentials (ERPs) to negative and neutral target words were measured during a lexical decision task in an IRP paradigm. Temporal and spatial versions of principal components analyses were used to detect and quantify those ERP components associated with IRP. A source localization procedure provided information on the neural origin of these components. Behavioural analyses showed that reaction times to repeated negative and neutral words differed from those to unrepeated negative and neutral words, respectively. However, the interaction between repetition and emotion was only marginally significant. In contrast, ERP analyses revealed specific IRP effects for negative words: Repeated negative words elicited reduced P120/enhanced N170 effects and weaker activation suppression in the left inferior frontal gyrus than did unrepeated negative words. These results suggest that a word's negative content captures attention interfering with IRP mechanisms, possibly at an early semantic stage of processing.

Word frequency modulates the processing of emotional words: convergent behavioral and electrophysiological data.

The processing of high frequency (HF) words is speeded as compared to the processing of low frequency (LF) words, which is known as the word frequency effect. This effect has been suggested to occur at either a lexical access or in a decision processing stage. Previous work has shown that word frequency influenced the processing of emotional content at both neural and behavioral levels. However, the results of these studies lead to discrepant findings because some of the variables that have shown to impact the processing of affective information were not always controlled. In order to make a better characterization of frequency effects on emotional word processing, event related potentials (ERPs) and reaction times to HF and LF negative and neutral nouns were measured as participants performed a lexical decision task. Temporal and spatial component analyses were used to detect and quantify, in a reliable way, those components associated with the interaction between word frequency and emotion. LF negative nouns were recognized faster and more accurately than LF neutral nouns whereas no differences were found in the HF word comparison. Also, LF neutral words elicited reduced amplitudes in a late positive component (P450) as compared to LF negative words. These findings might be reflecting a different involvement of attentional mechanisms during the evaluation of lexical information that benefits the processing of LF negative nouns.

Emotion modulates language production during covert picture naming.

Previous studies have shown that emotional content modulates the activity of several components of the event-related potentials during word comprehension. However, little is known about the impact of affective information on the different processing stages involved in word production. In the present study we aimed to investigate the influence of positive and negative emotions in phonological encoding, a process that have been shown to take place between 300 and 450 ms in previous studies. Participants performed letter searching in a picture naming task. It was found that grapheme monitoring in positive and negative picture names was associated with slower reaction times and enhanced amplitudes of a positive component around 400 ms as compared to monitoring letters in neutral picture names. We propose that this modulation reflects a disruption in phonological encoding processes as a consequence of the capture of attention by affective content. Grapheme monitoring in positive picture names also elicited higher amplitudes than letter searching in neutral image names in a positive component around 100 ms. This amplitude enhancement might be interpreted as a manifestation of the 'positive offset' during conceptual preparation processes. The results of a control experiment with a passive viewing task showed that both effects cannot be simply attributed to the processing of the emotional images per se. Overall, it seems that emotion modulates word production at several processing stages.

Looking at emotional words is not the same as reading emotional words: Behavioral and neural correlates.

Recent research suggests that the allocation of attentional resources to emotional content during word processing might be sensitive to task requirements. This question was investigated in two tasks with similar instructions. The stimuli were positive, negative, and neutral nouns. Participants had to identify meaningful words embedded in a stream of non-recognizable stimuli (task 1) or pseudowords (task 2). Task 1 could be successfully performed on the basis of the perceptual features whereas a lexico-semantic analysis was required in task 2. Effects were found only in task 2. Positive nouns were identified faster, with fewer errors and elicited larger amplitude in an early negativity. Also, the amplitude of a late positivity was larger for both positive and negative nouns than for neutral nouns. It is concluded that some degree of linguistic processing is needed to direct attention to the affective content during word processing.