Cortical paired associative stimulation shows impaired plasticity of inhibition networks as a function of chronic alcohol use.

BACKGROUND: Response inhibition - or the ability to withhold a suboptimal response - relies on the efficacy of fronto-striatal networks, and is impaired in neuropsychiatric disorders including addiction. Cortical paired associative stimulation (cPAS) is a form of transcranial magnetic stimulation (TMS) which can strengthen neuronal connections via spike-timing-dependent plasticity mechanisms. Here, we used cPAS targeting the fronto-striatal inhibitory network to modulate performance on a response inhibition measure in chronic alcohol use. METHODS: Fifty-five participants (20 patients with a formal alcohol use disorder (AUD) diagnosis (26-74 years, 6[30%] females) and 20 matched healthy controls (HCs) (27-73 years, 6[30%] females) within a larger sample of 35 HCs (23-84 years, 11[31.4%] females) underwent two randomized sessions of cPAS 1-week apart: right inferior frontal cortex stimulation preceding right presupplementary motor area stimulation by either 4 ms (excitation condition) or 100 ms (control condition), and were subsequently administered the Stop Signal Task (SST) in both sessions. RESULTS: HCs showed decreased stop signal reaction time in the excitation condition (t(19) = -3.01, p = 0.007, [CIs]:-35.6 to -6.42); this facilitatory effect was not observed for AUD (F(1,31) = 9.57, p = 0.004, CIs: -68.64 to -14.11). Individually, rates of SST improvement were substantially higher for healthy (72%) relative to AUD (13.6%) groups (OR: 2.33, p = 0.006, CIs:-3.34 to -0.55). CONCLUSION: In line with previous findings, cPAS improved response inhibition in healthy adults by strengthening the fronto-striatal network through putative long-term potentiation-like plasticity mechanisms. Furthermore, we identified a possible marker of impaired cortical excitability, and, thus, diminished capacity for cPAS-induced neuroplasticity in AUD with direct implications to a disorder-relevant cognitive process.

Revisiting deficits in threat and safety appraisal in obsessive-compulsive disorder.

Current behavioural treatment of obsessive-compulsive disorder (OCD) is informed by fear conditioning and involves iteratively re-evaluating previously threatening stimuli as safe. However, there is limited research investigating the neurobiological response to conditioning and reversal of threatening stimuli in individuals with OCD. A clinical sample of individuals with OCD (N = 45) and matched healthy controls (N = 45) underwent functional magnetic resonance imaging. While in the scanner, participants completed a well-validated fear reversal task and a resting-state scan. We found no evidence for group differences in task-evoked brain activation or functional connectivity in OCD. Multivariate analyses encompassing all participants in the clinical and control groups suggested that subjective appraisal of threatening and safe stimuli were associated with a larger difference in brain activity than the contribution of OCD symptoms. In particular, we observed a brain-behaviour continuum whereby heightened affective appraisal was related to increased bilateral insula activation during the task (r = 0.39, pFWE = .001). These findings suggest that changes in conditioned threat-related processes may not be a core neurobiological feature of OCD and encourage further research on the role of subjective experience in fear conditioning.

Time-locked acute alpha-frequency stimulation of subthalamic nuclei during the evaluation of emotional stimuli and its effect on power modulation.

Introduction: Deep brain stimulation (DBS) studies in Parkinson's Disease (PD) targeting the subthalamic nucleus (STN) have characterized its spectral properties across cognitive processes. In emotional evaluation tasks, specific alpha frequency (8-12 Hz) event-related de-synchronization (ERD) (reduced power) has been demonstrated. The time-locked stimulation of STN relative to stimuli onset has shown subjective positive valence shifts with 10 Hz but not with 130 Hz. However, neurophysiological effects of stimulation on power modulation have not been investigated. We aim to investigate effects of acute stimulation of the right STN on concurrent power modulation in the contralateral STN and frontal scalp EEG. From our previous study, we had a strong a priori hypothesis that negative imagery without stimulation would be associated with alpha ERD; negative imagery with 130 Hz stimulation would be also associated with alpha ERD given the lack of its effect on subjective valence ratings; negative imagery with 10 Hz stimulation was to be associated with enhanced alpha power given the shift in behavioral valence ratings. Methods: Twenty-four subjects with STN DBS underwent emotional picture-viewing tasks comprising neutral and negative pictures. In a subset of these subjects, the negative images were associated with time-locked acute stimulation at either 10 or 130 Hz. Power of signals was estimated relative to the baseline and subjected to non-parametric statistical testing. Results: As hypothesized, in 130 Hz stimulation condition, we show a decrease in alpha power to negative vs. neutral images irrespective of stimulation. In contrast, this alpha power decrease was no longer evident in the negative 10 Hz stimulation condition consistent with a predicted increase in alpha power. Greater beta power in the 10 Hz stimulation condition along with correlations between beta power across the 10 Hz stimulation and unstimulated conditions suggest physiological and cognitive generalization effects. Conclusion: Acute alpha-specific frequency stimulation presumably was associated with a loss of this expected decrease or desynchronization in alpha power to negative images suggesting the capacity to facilitate the synchronization of alpha and enhance power. Acute time-locked stimulation has the potential to provide causal insights into the spectral frequencies and temporal dynamics of emotional processing.

Dynamic interactions between anterior insula and anterior cingulate cortex link perceptual features and heart rate variability during movie viewing.

The dynamic integration of sensory and bodily signals is central to adaptive behaviour. Although the anterior cingulate cortex (ACC) and the anterior insular cortex (AIC) play key roles in this process, their context-dependent dynamic interactions remain unclear. Here, we studied the spectral features and interplay of these two brain regions using high-fidelity intracranial-EEG recordings from five patients (ACC: 13 contacts, AIC: 14 contacts) acquired during movie viewing with validation analyses performed on an independent resting intracranial-EEG dataset. ACC and AIC both showed a power peak and positive functional connectivity in the gamma (30-35 Hz) frequency while this power peak was absent in the resting data. We then used a neurobiologically informed computational model investigating dynamic effective connectivity asking how it linked to the movie's perceptual (visual, audio) features and the viewer's heart rate variability (HRV). Exteroceptive features related to effective connectivity of ACC highlighting its crucial role in processing ongoing sensory information. AIC connectivity was related to HRV and audio emphasising its core role in dynamically linking sensory and bodily signals. Our findings provide new evidence for complementary, yet dissociable, roles of neural dynamics between the ACC and the AIC in supporting brain-body interactions during an emotional experience.

Frequency dependent emotion differentiation and directional coupling in amygdala, orbitofrontal and medial prefrontal cortex network with intracranial recordings.

The amygdala, orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) form a crucial part of the emotion circuit, yet their emotion induced responses and interactions have been poorly investigated with direct intracranial recordings. Such high-fidelity signals can uncover precise spectral dynamics and frequency differences in valence processing allowing novel insights on neuromodulation. Here, leveraging the unique spatio-temporal advantages of intracranial electroencephalography (iEEG) from a cohort of 35 patients with intractable epilepsy (with 71 contacts in amygdala, 31 in OFC and 43 in mPFC), we assessed the spectral dynamics and interactions between the amygdala, OFC and mPFC during an emotional picture viewing task. Task induced activity showed greater broadband gamma activity in the negative condition compared to positive condition in all the three regions. Similarly, beta activity was increased in the negative condition in the amygdala and OFC while decreased in mPFC. Furthermore, beta activity of amygdala showed significant negative association with valence ratings. Critically, model-based computational analyses revealed unidirectional connectivity from mPFC to the amygdala and bidirectional communication between OFC-amygdala and OFC-mPFC. Our findings provide direct neurophysiological evidence for a much-posited model of top-down influence of mPFC over amygdala and a bidirectional influence between OFC and the amygdala. Altogether, in a relatively large sample size with human intracranial neuronal recordings, we highlight valence-dependent spectral dynamics and dyadic coupling within the amygdala-mPFC-OFC network with implications for potential targeted neuromodulation in emotion processing.

Mechanisms of imbalanced frontostriatal functional connectivity in obsessive-compulsive disorder.

The diagnosis of obsessive-compulsive disorder (OCD) has been linked with changes in frontostriatal resting-state connectivity. However, replication of prior findings is lacking, and the mechanistic understanding of these effects is incomplete. To confirm and advance knowledge on changes in frontostriatal functional connectivity in OCD, participants with OCD and matched healthy controls underwent resting-state functional, structural and diffusion neuroimaging. Functional connectivity changes in frontostriatal systems were here replicated in individuals with OCD (n = 52) compared with controls (n = 45). OCD participants showed greater functional connectivity (t = 4.3, PFWE = 0.01) between the nucleus accumbens (NAcc) and the orbitofrontal cortex (OFC) but lower functional connectivity between the dorsal putamen and lateral prefrontal cortex (t = 3.8, PFWE = 0.04) relative to controls. Computational modelling suggests that NAcc-OFC connectivity changes reflect an increased influence of NAcc over OFC activity and reduced OFC influence over NAcc activity (posterior probability, Pp > 0.66). Conversely, dorsal putamen showed reduced modulation over lateral prefrontal cortex activity (Pp > 0.90). These functional deregulations emerged on top of a generally intact anatomical substrate. We provide out-of-sample replication of opposite changes in ventro-anterior and dorso-posterior frontostriatal connectivity in OCD and advance the understanding of the neural underpinnings of these functional perturbations. These findings inform the development of targeted therapies normalizing frontostriatal dynamics in OCD.

Power signatures of habenular neuronal signals in patients with bipolar or unipolar depressive disorders correlate with their disease severity.

The habenula is an epithalamic structure implicated in negative reward mechanisms and plays a downstream modulatory role in regulation of dopaminergic and serotonergic functions. Human and animal studies show its hyperactivity in depression which is curtailed by the antidepressant response of ketamine. Deep brain stimulation of habenula (DBS) for major depression have also shown promising results. However, direct neuronal activity of habenula in human studies have rarely been reported. Here, in a cross-sectional design, we acquired both spontaneous resting state and emotional task-induced neuronal recordings from habenula from treatment resistant depressed patients undergoing DBS surgery. We first characterise the aperiodic component (1/f slope) of the power spectrum, interpreted to signify excitation-inhibition balance, in resting and task state. This aperiodicity for left habenula correlated between rest and task and which was significantly positively correlated with depression severity. Time-frequency responses to the emotional picture viewing task show condition differences in beta and gamma frequencies for left habenula and alpha for right habenula. Notably, alpha activity for right habenula was negatively correlated with depression severity. Overall, from direct habenular recordings, we thus show findings convergent with depression models of aberrant excitatory glutamatergic output of the habenula driving inhibition of monoaminergic systems.

Data-driven analysis of facial thermal responses and multimodal physiological consistency among subjects.

Facial infra-red imaging (IRI) is a contact-free technique complimenting the traditional psychophysiological measures to characterize physiological profile. However, its full potential in affective research is arguably unmet due to the analytical challenges it poses. Here we acquired facial IRI data, facial expressions and traditional physiological recordings (heart rate and skin conductance) from healthy human subjects whilst they viewed a 20-min-long unedited emotional movie. We present a novel application of motion correction and the results of spatial independent component analysis of the thermal data. Three distinct spatial components are recovered associated with the nose, the cheeks and respiration. We first benchmark this methodology against a traditional nose-tip region-of-interest based technique showing an expected similarity of signals extracted by these methods. We then show significant correlation of all the physiological responses across subjects, including the thermal signals, suggesting common dynamic shifts in emotional state induced by the movie. In sum, this study introduces an innovative approach to analyse facial IRI data and highlights the potential of thermal imaging to robustly capture emotion-related changes induced by ecological stimuli.

A prospective cohort study of prodromal Alzheimer's disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA).

This prospective cohort study, "Prospective Imaging Study of Ageing: Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

Movie viewing elicits rich and reliable brain state dynamics.

Adaptive brain function requires that sensory impressions of the social and natural milieu are dynamically incorporated into intrinsic brain activity. While dynamic switches between brain states have been well characterised in resting state acquisitions, the remodelling of these state transitions by engagement in naturalistic stimuli remains poorly understood. Here, we show that the temporal dynamics of brain states, as measured in fMRI, are reshaped from predominantly bistable transitions between two relatively indistinct states at rest, toward a sequence of well-defined functional states during movie viewing whose transitions are temporally aligned to specific features of the movie. The expression of these brain states covaries with different physiological states and reflects subjectively rated engagement in the movie. In sum, a data-driven decoding of brain states reveals the distinct reshaping of functional network expression and reliable state transitions that accompany the switch from resting state to perceptual immersion in an ecologically valid sensory experience.

Intracranial-EEG evidence for medial temporal pole driving amygdala activity induced by multi-modal emotional stimuli.

The temporal pole (TP) is an associative cortical region required for complex cognitive functions such as social and emotional cognition. However, mapping the TP with functional magnetic resonance imaging is technically challenging and thus understanding its interaction with other key emotional circuitry, such as the amygdala, remains elusive. We exploited the unique advantages of stereo-electroencephalography (sEEG) to assess the responses of the TP and the amygdala during the perception of emotionally salient stimuli of pictures, music and movies. These stimuli consistently elicited high gamma responses (70-140 Hz) in both the TP and the amygdala, accompanied by functional connectivity in the low frequency range (2-12 Hz). Computational analyses suggested that the TP drove this effect in the theta frequency range, modulated by the emotional valence of the stimuli. Notably, cross-frequency analysis indicated the phase of theta oscillations in the TP modulated the amplitude of high gamma activity in the amygdala. These results were reproducible across three types of sensory inputs including naturalistic stimuli. Our results suggest that multimodal emotional stimuli induce a hierarchical influence of the TP over the amygdala.

Naturalistic Stimuli in Neuroscience: Critically Acclaimed.

Cognitive neuroscience has traditionally focused on simple tasks, presented sparsely and using abstract stimuli. While this approach has yielded fundamental insights into functional specialisation in the brain, its ecological validity remains uncertain. Do these tasks capture how brains function 'in the wild', where stimuli are dynamic, multimodal, and crowded? Ecologically valid paradigms that approximate real life scenarios, using stimuli such as films, spoken narratives, music, and multiperson games emerged in response to these concerns over a decade ago. We critically appraise whether this approach has delivered on its promise to deliver new insights into brain function. We highlight the challenges, technological innovations, and clinical opportunities that are required should this field meet its full potential.

Detecting changes in facial temperature induced by a sudden auditory stimulus based on deep learning-assisted face tracking.

Thermal Imaging (Infrared-Imaging-IRI) is a promising new technique for psychophysiological research and application. Unlike traditional physiological measures (like skin conductance and heart rate), it is uniquely contact-free, substantially enhancing its ecological validity. Investigating facial regions and subsequent reliable signal extraction from IRI data is challenging due to head motion artefacts. Exploiting its potential thus depends on advances in analytical methods. Here, we developed a novel semi-automated thermal signal extraction method employing deep learning algorithms for facial landmark identification. We applied this method to physiological responses elicited by a sudden auditory stimulus, to determine if facial temperature changes induced by a stimulus of a loud sound can be detected. We compared thermal responses with psycho-physiological sensor-based tools of galvanic skin response (GSR) and electrocardiography (ECG). We found that the temperatures of selected facial regions, particularly the nose tip, significantly decreased after the auditory stimulus. Additionally, this response was quite rapid at around 4-5 seconds, starting less than 2 seconds following the GSR changes. These results demonstrate that our methodology offers a sensitive and robust tool to capture facial physiological changes with minimal manual intervention and manual pre-processing of signals. Newer methodological developments for reliable temperature extraction promise to boost IRI use as an ecologically-valid technique in social and affective neuroscience.

Effective connectivity of the anterior hippocampus predicts recollection confidence during natural memory retrieval.

Human interactions with the world are influenced by memories of recent events. This effect, often triggered by perceptual cues, occurs naturally and without conscious effort. However, the neuroscience of involuntary memory in a dynamic milieu has received much less attention than the mechanisms of voluntary retrieval with deliberate purpose. Here, we investigate the neural processes driven by naturalistic cues that relate to, and presumably trigger the retrieval of recent experiences. Viewing the continuation of recently viewed clips evokes greater bilateral activation in anterior hippocampus, precuneus and angular gyrus than naïve clips. While these regions manifest reciprocal connectivity, continued viewing specifically modulates the effective connectivity from the anterior hippocampus to the precuneus. The strength of this modulation predicts participants' confidence in later voluntary recall of news details. Our study reveals network mechanisms of dynamic, involuntary memory retrieval and its relevance to metacognition in a rich context resembling everyday life.

Distinct Cerebellar Contributions to Cognitive-Perceptual Dynamics During Natural Viewing.

The crucial role of the cerebellum in motor learning and coordination is very well known. Considerable interest has recently shifted toward its contribution to nonmotor tasks, such as working memory, emotion, and language. However, the cognitive role and functional subdivisions of the cerebellum, particularly in dynamic, ecologically realistic contexts, are not yet established. By analyzing functional neuroimaging data acquired while participants viewed a short dramatic movie, we found that posterior and inferior cerebellar regions are reliably engaged in dynamic perceptual and affective processes with no explicit motor component. These cerebellar regions show significant relevance to visual salience and unexpected turning points of the movie. Our results demonstrate that distinct functional subdivisions of the cerebellum are robustly engaged in real-life cognitive processes, playing specific roles through a dynamic interaction with higher order regions in the cerebral cortex.

Automatic and Controlled Semantic Retrieval: TMS Reveals Distinct Contributions of Posterior Middle Temporal Gyrus and Angular Gyrus.

Semantic retrieval involves both (1) automatic spreading activation between highly related concepts and (2) executive control processes that tailor this activation to suit the current context or goals. Two structures in left temporoparietal cortex, angular gyrus (AG) and posterior middle temporal gyrus (pMTG), are thought to be crucial to semantic retrieval and are often recruited together during semantic tasks; however, they show strikingly different patterns of functional connectivity at rest (coupling with the "default mode network" and "frontoparietal control system," respectively). Here, transcranial magnetic stimulation (TMS) was used to establish a causal yet dissociable role for these sites in semantic cognition in human volunteers. TMS to AG disrupted thematic judgments particularly when the link between probe and target was strong (e.g., a picture of an Alsatian with a bone), and impaired the identification of objects at a specific but not a superordinate level (for the verbal label "Alsatian" not "animal"). In contrast, TMS to pMTG disrupted thematic judgments for weak but not strong associations (e.g., a picture of an Alsatian with razor wire), and impaired identity matching for both superordinate and specific-level labels. Thus, stimulation to AG interfered with the automatic retrieval of specific concepts from the semantic store while stimulation of pMTG impaired semantic cognition when there was a requirement to flexibly shape conceptual activation in line with the task requirements. These results demonstrate that AG and pMTG make a dissociable contribution to automatic and controlled aspects of semantic retrieval. SIGNIFICANCE STATEMENT: We demonstrate a novel functional dissociation between the angular gyrus (AG) and posterior middle temporal gyrus (pMTG) in conceptual processing. These sites are often coactivated during neuroimaging studies using semantic tasks, but their individual contributions are unclear. Using transcranial magnetic stimulation and tasks designed to assess different aspects of semantics (item identity and thematic matching), we tested two alternative theoretical accounts. Neither site showed the pattern expected for a "thematic hub" (i.e., a site storing associations between concepts) since stimulation disrupted both tasks. Instead, the data indicated that pMTG contributes to the controlled retrieval of conceptual knowledge, while AG is critical for the efficient automatic retrieval of specific semantic information.