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.

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.

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.

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.

Acute Time-Locked Alpha Frequency Subthalamic Stimulation Reduces Negative Emotional Bias in Parkinson's Disease.

BACKGROUND: Emotional processing is a core cognitive process cutting across neuropsychiatric disorders. Understanding the neurophysiological features underlying depressive symptoms and their sensitivity to modulation is critical to modifying emotional bias. The subthalamic nucleus (STN), targeted in Parkinson's disease, shows a late alpha desynchronization to affective stimuli. We targeted this alpha desynchronization using a novel stimulation protocol asking if brief alpha (10 Hz) frequency stimulation time-locked to unpleasant imagery might influence subjective emotion. METHODS: A total of 27 patients with Parkinson's disease were recruited. The first study tested patients (n = 16) on affective stimuli with STN local field potential recordings assessed bilaterally without stimulation. In the second study, patients (n = 24) were tested on two affective tasks comparing negative and neutral stimuli paired with acute right-STN stimulation, with one of the negative conditions stimulated briefly for 1 second at either 130 Hz or 10 Hz. The subjects rated valence and arousal of negative and neutral stimuli. RESULTS: We confirmed greater alpha desynchronization in both negative and positive affect relative to neutral in the right STN. Using acute stimulation of the right STN, we show a critical interaction effect between ratings, stimulation, and frequency; alpha frequency stimulation increased the subjective pleasantness of negative imagery, particularly with ventromedial contacts. Higher depression scores were associated with a positive bias to 10-Hz but not 130-Hz stimulation. CONCLUSIONS: We highlight the potential of brief alpha frequency subthalamic stimulation to reduce negative emotional bias. This finding provides mechanistic insights underlying subjective emotional valence and has implications for the management of depression using neuromodulation.

Shifting uncertainty intolerance: methylphenidate and attention-deficit hyperactivity disorder.

Risk evaluation is a critical component of decision making. Risk tolerance is relevant in both daily decisions and pathological disorders such as attention-deficit hyperactivity disorder (ADHD), where impulsivity is a cardinal symptom. Methylphenidate, a commonly prescribed drug in ADHD, improves attention but has mixed reports on risk-based decision making. Using a double-blinded placebo protocol, we studied the risk attitudes of ADHD patients and age-matched healthy volunteers while performing the 2-step sequential learning task and examined the effect of methylphenidate on their choices. We then applied a novel computational analysis using the hierarchical drift-diffusion model to extract parameters such as threshold ('a'-amount of evidence accumulated before making a decision), drift rate ('v'-information processing speed) and response bias ('z' apriori bias towards a specific choice) focusing specifically on risky choice preference. Critically, we show that ADHD patients on placebo have an apriori bias towards risky choices compared to controls. Furthermore, methylphenidate enhanced preference towards risky choices (higher apriori bias) in both groups but had a significantly greater effect in the patient population independent of clinical scores. Thus, methylphenidate appears to shift tolerance towards risky uncertain choices possibly mediated by prefrontal dopaminergic and noradrenergic modulation. We emphasise the utility of computational models in detecting underlying processes. Our findings have implications for subtle yet differential effects of methylphenidate on ADHD compared to healthy population.

Impulsivity and craving in subjects with opioid use disorder on methadone maintenance treatment.

BACKGROUND: Methadone maintenance treatment (MMT) is effective in decreasing opioid use or facilitating abstinence. Previous studies using small opioid use disorder samples suggest that cognitive impairments including impulsivity and executive functions may partially improve on MMT, but a range of deficits may persist. However, systematic assessments with larger samples are needed to confirm the profile of cognitive functions on MMT. METHODS: We assessed four types of impulsivity (delay discounting, reflection impulsivity, risk taking and motoric impulsivity), executive functioning (spatial working memory, paired associative learning and strategic planning) and drug cue-induced craving in a relatively large population (115 MMT patients, 115 healthy controls). The relationships between impulsivity, drug cue-induced craving and addiction-related variables were also assessed. RESULTS: Delay discounting, as well as drug cue-induced craving was increased in patients, while motoric impulsivity was lower than in controls. Paired associative learning was additionally impaired, which was explained by increased depression and anxiety levels in patients. Within the MMT group, the delay discounting and drug-cue induced craving scores were positively correlated with self-reported urgency, but unrelated to methadone dosage, duration on methadone, withdrawal symptoms, or presence of nicotine dependence. CONCLUSIONS: Our findings highlight increased delay discounting and cue-induced craving in MMT patients suggesting a potential role for trait effects in delay discounting. Although previous smaller studies have shown impaired executive function, in our large sample size on chronic MMT we only observed impaired associative learning related to depressive and anxiety symptoms highlighting a role for managing comorbid symptoms to further optimize cognitive function.

Addictions NeuroImaging Assessment (ANIA): Towards an integrative framework for alcohol use disorder.

Alcohol misuse and addiction are major international public health issues. Addiction can be characterized as a disorder of aberrant neurocircuitry interacting with environmental, genetic and social factors. Neuroimaging in alcohol misuse can thus provide a critical window into underlying neural mechanisms, highlighting possible treatment targets and acting as clinical biomarkers for predicting risk and treatment outcomes. This neuroimaging review on alcohol misuse in humans follows the Addictions Neuroclinical Assessment (ANA) that proposes incorporating three functional neuroscience domains integral to the neurocircuitry of addiction: incentive salience and habits, negative emotional states, and executive function within the context of the addiction cycle. Here we review and integrate multiple imaging modalities focusing on underlying cognitive processes such as reward anticipation, negative emotionality, cue reactivity, impulsivity, compulsivity and executive function. We highlight limitations in the literature and propose a model forward in the use of neuroimaging as a tool to understanding underlying mechanisms and potential clinical applicability for phenotyping of heterogeneity and predicting risk and treatment outcomes.

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity.

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). Although many mechanisms have been suggested, a decisive root cause of this cell loss is unknown. A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells compared to other dopaminergic clusters; the other is the SubThalamic Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter hypothesis computationally, we developed a spiking neuron network-model of SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in 'stress' variable; when the stress in a SNc neuron exceeds a stress threshold, the neuron dies. The model shows that the interaction between SNc and STN involves a positive-feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway-effect, leading to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned mechanisms of SNc cell loss. Our simulation results show that the excitotoxic cause of SNc cell loss might initiate by weak-excitotoxicity mediated by energy deficit, followed by strong-excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies were simulated to test their efficacy in slowing down SNc cell loss. Among them, glutamate inhibition, dopamine restoration, subthalamotomy and deep brain stimulation showed superior neuroprotective-effects in the proposed model.

The ease and sureness of a decision: evidence accumulation of conflict and uncertainty.

The likelihood of an outcome (uncertainty or sureness) and the similarity between choices (conflict or ease of a decision) are often critical to decision-making. We often ask ourselves: how likely are we to win or lose? And how different is this option's likelihood from the other? Uncertainty is a characteristic of the stimulus and conflict between stimuli, but these dissociable processes are often confounded. Here, applying a novel hierarchical drift diffusion approach, we study their interaction using a sequential learning task in healthy volunteers and pathological groups characterized by compulsive behaviours, by posing it as an evidence accumulation problem. The variables, Conflict (difficult or easy; difference between reward probabilities of the stimuli) and Uncertainty (low, medium or high; inverse U-shaped probability-uncertainty function) were then used to extract threshold ('a', amount of evidence accumulated before making a decision) and drift rate ('v', information processing speed) parameters. Critically, when a decision was both difficult (high conflict) and uncertain, relative to other conditions, healthy volunteers unexpectedly accumulated less evidence with lower decision thresholds and accuracy rates at chance levels. In contrast, patients with obsessive-compulsive disorder had slower processing speeds during these difficult uncertain decisions; yet, despite this more cautious approach, performed suboptimally with poorer accuracy relative to healthy volunteers below that of chance level. Thus, faced with a difficult uncertain decision, healthy controls are capable of rapid possibly random decisions, displaying almost a willingness to 'walk away', whereas those with obsessive compulsive disorder become more deliberative and cautious but despite appearing to learn the differential contingencies, still perform poorly. These observations might underlie disordered behaviours characterized by pathological uncertainty or doubt despite compulsive checking with impaired performance. In contrast, alcohol-dependent subjects show a different pattern relative to healthy controls with difficulties in adjusting their behavioural patterns with slower drift rates or processing speed despite decisions being easy or low conflict. We emphasize the multidimensional nature of compulsive behaviours and the utility of computational models in detecting subtle underlying processes relative to behavioural measures. These observations have implications for targeted behavioural interventions for specific cognitive impairments across psychiatric disorders.

The many facets of dopamine: Toward an integrative theory of the role of dopamine in managing the body's energy resources.

In neuroscience literature, dopamine is often considered as a pleasure chemical of the brain. Dopaminergic neurons respond to rewarding stimuli which include primary rewards like opioids or food, or more abstract forms of reward like cash rewards or pictures of pretty faces. It is this reward-related aspect of dopamine, particularly its association with reward prediction error, that is highlighted by a large class of computational models of dopamine signaling. Dopamine is also a neuromodulator, controlling synaptic plasticity in several cortical and subcortical areas. But dopamine's influence is not limited to the nervous system; its effects are also found in other physiological systems, particularly the circulatory system. Importantly, dopamine agonists have been used as a drug to control blood pressure. Is there a theoretical, conceptual connection that reconciles dopamine's effects in the nervous system with those in the circulatory system? This perspective article integrates the diverse physiological roles of dopamine and provides a simple theoretical framework arguing that its reward related function regulates the processes of energy consumption and acquisition in the body. We conclude by suggesting that energy-related book-keeping of the body at the physiological level is the common motif that links the many facets of dopamine and its functions.

Electrode Position and Current Amplitude Modulate Impulsivity after Subthalamic Stimulation in Parkinsons Disease-A Computational Study.

Background: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) is highly effective in alleviating motor symptoms of Parkinson's disease (PD) which are not optimally controlled by dopamine replacement therapy. Clinical studies and reports suggest that STN-DBS may result in increased impulsivity and de novo impulse control disorders (ICD). Objective/Hypothesis: We aimed to compare performance on a decision making task, the Iowa Gambling Task (IGT), in healthy conditions (HC), untreated and medically-treated PD conditions with and without STN stimulation. We hypothesized that the position of electrode and stimulation current modulate impulsivity after STN-DBS. Methods: We built a computational spiking network model of basal ganglia (BG) and compared the model's STN output with STN activity in PD. Reinforcement learning methodology was applied to simulate IGT performance under various conditions of dopaminergic and STN stimulation where IGT total and bin scores were compared among various conditions. Results: The computational model reproduced neural activity observed in normal and PD conditions. Untreated and medically-treated PD conditions had lower total IGT scores (higher impulsivity) compared to HC (P < 0.0001). The electrode position that happens to selectively stimulate the part of the STN corresponding to an advantageous panel on IGT resulted in de-selection of that panel and worsening of performance (P < 0.0001). Supratherapeutic stimulation amplitudes also worsened IGT performance (P < 0.001). Conclusion(s): In our computational model, STN stimulation led to impulsive decision making in IGT in PD condition. Electrode position and stimulation current influenced impulsivity which may explain the variable effects of STN-DBS reported in patients.

Probing the Role of Medication, DBS Electrode Position, and Antidromic Activation on Impulsivity Using a Computational Model of Basal Ganglia.

Everyday, we encounter situations where available choices are nearly equally rewarding (high conflict) calling for some tough decision making. Experimental recordings showed that the activity of Sub Thalamic Nucleus (STN) increases during such situations providing the extra time needed to make the right decision, teasing apart the most rewarding choice from the runner up closely trailing behind. This prolonged deliberation necessary for decision making under high conflict was absent in Parkinson's disease (PD) patients who underwent Deep Brain Stimulation (DBS) surgery of STN. In an attempt to understand the underlying cause of such adverse response, we built a 2D spiking network model (50 × 50 lattice) of Basal ganglia incorporating the key nuclei. Using the model we studied the Probabilistic learning task (PLT) in untreated, treated (L-Dopa and Dopamine Agonist) and STN-DBS PD conditions. Based on the experimental observation that dopaminergic activity is analogous to temporal difference (TD) and induces cortico-striatal plasticity, we introduced learning in the cortico-striatal weights. The results show that healthy and untreated conditions of PD model were able to more or less equally select (avoid) the rewarding (punitive) choice, a behavior that was absent in treated PD condition. The time taken to select a choice in high conflict trials was high in normal condition, which is in agreement with experimental results. The treated PD (Dopamine Agonist) patients made impulsive decisions (small reaction time) which in turn led to poor performance. The underlying cause of the observed impulsivity in DBS patients was studied in the model by (1) varying the electrode position within STN, (2) causing antidromic activation of GPe neurons. The effect of electrode position on reaction time was analyzed by studying the activity of STN neurons where, a decrease in STN neural activity was observed for certain electrode positions. We also observed that a higher antidromic activation of GPe neurons does not impact the learning ability but decreases reaction time as reported in DBS patients. These results suggest a probable role of electrode and antidromic activation in modulating the STN activity and eventually affecting the patient's performance on PLT.

A spiking Basal Ganglia model of synchrony, exploration and decision making.

To make an optimal decision we need to weigh all the available options, compare them with the current goal, and choose the most rewarding one. Depending on the situation an optimal decision could be to either "explore" or "exploit" or "not to take any action" for which the Basal Ganglia (BG) is considered to be a key neural substrate. In an attempt to expand this classical picture of BG function, we had earlier hypothesized that the Indirect Pathway (IP) of the BG could be the subcortical substrate for exploration. In this study we build a spiking network model to relate exploration to synchrony levels in the BG (which are a neural marker for tremor in Parkinson's disease). Key BG nuclei such as the Sub Thalamic Nucleus (STN), Globus Pallidus externus (GPe) and Globus Pallidus internus (GPi) were modeled as Izhikevich spiking neurons whereas the Striatal output was modeled as Poisson spikes. The model is cast in reinforcement learning framework with the dopamine signal representing reward prediction error. We apply the model to two decision making tasks: a binary action selection task (similar to one used by Humphries et al., 2006) and an n-armed bandit task (Bourdaud et al., 2008). The model shows that exploration levels could be controlled by STN's lateral connection strength which also influenced the synchrony levels in the STN-GPe circuit. An increase in STN's lateral strength led to a decrease in exploration which can be thought as the possible explanation for reduced exploratory levels in Parkinson's patients. Our simulations also show that on complete removal of IP, the model exhibits only Go and No-Go behaviors, thereby demonstrating the crucial role of IP in exploration. Our model provides a unified account for synchronization, action section, and explorative behavior.