Dorsal-to-ventral imbalance in the superior longitudinal fasciculus mediates methylphenidate's effect on beta oscillations in ADHD.

While pharmacological treatment with methylphenidate (MPH) is a first line intervention for ADHD, its mechanisms of action have yet to be elucidated. We here seek to identify the white matter tracts that mediate MPH's effect on beta oscillations. We implemented a double-blind placebo-controlled crossover design, where boys diagnosed with ADHD underwent behavioral and MEG measurements during a spatial attention task while on and off MPH. The results were compared with an age/IQ-matched control group. Estimates of white matter tracts were obtained using diffusion tensor imaging (DTI). Via a stepwise model selection strategy, we identified the fiber tracts (regressors) significantly predicting values of the dependent variables of interest (i.e., oscillatory power, behavioral performance, and clinical symptoms): the anterior thalamic radiation (ATR), the superior longitudinal fasciculus ("parietal endings") (SLFp), and superior longitudinal fasciculus ("temporal endings") (SLFt). ADHD symptoms severity was associated with lower fractional anisotropy (FA) within the ATR. In addition, individuals with relatively higher FA in SLFp compared to SLFt, led to stronger behavioral effects of MPH in the form of faster and more accurate responses. Furthermore, the same parietotemporal FA gradient explained the effects of MPH on beta modulation: subjects with ADHD exhibiting higher FA in SLFp compared to SLFt also displayed greater effects of MPH on beta power during response preparation. Our data suggest that the behavioral deficits and aberrant oscillatory modulations observed in ADHD depend on a possibly detrimental structural connectivity imbalance within the SLF, caused by a diffusivity gradient in favor of parietal rather than temporal, fiber tracts.

Catecholaminergic modulation of trust decisions.

RATIONALE: Trust is a key component of social interactions. In order to assess the trustworthiness of others, people rely on both information learned from previous encounters, as well as on implicit biases associated with specific facial features. OBJECTIVE: Here, we investigated the role of catecholamine (dopamine and noradrenaline) transmission on trust decisions as a function of both experienced behavior and facial features. METHODS: To increase catecholamine levels, methylphenidate (MPH, i.e., Ritalin®, 20 mg) was administered to participants (N = 24) prior to their playing a well-studied economic task, namely the Trust Game (Berg et al. 1995). We measured the amount of money invested with a variety of game partners. Across game partners, we manipulated two aspects of trust: the facial trust level (high facial trust, low facial trust, and non-social) and the likelihood of reciprocation (high, low). RESULTS: Results demonstrated no main effect of MPH on investments, but rather a selective lowering of investments under MPH as compared with placebo with the game partners who were low on facial trustworthiness and were low reciprocators. CONCLUSION: These results provide evidence that MPH administration impacts social trust decision-making, but does so in a context-specific manner.

Dopaminergic Drug Effects on Probability Weighting during Risky Decision Making.

Dopamine has been associated with risky decision-making, as well as with pathological gambling, a behavioral addiction characterized by excessive risk-taking behavior. However, the specific mechanisms through which dopamine might act to foster risk-taking and pathological gambling remain elusive. Here we test the hypothesis that this might be achieved, in part, via modulation of subjective probability weighting during decision making. Human healthy controls (n = 21) and pathological gamblers (n = 16) played a decision-making task involving choices between sure monetary options and risky gambles both in the gain and loss domains. Each participant played the task twice, either under placebo or the dopamine D2/D3 receptor antagonist sulpiride, in a double-blind counterbalanced design. A prospect theory modelling approach was used to estimate subjective probability weighting and sensitivity to monetary outcomes. Consistent with prospect theory, we found that participants presented a distortion in the subjective weighting of probabilities, i.e., they overweighted low probabilities and underweighted moderate to high probabilities, both in the gain and loss domains. Compared with placebo, sulpiride attenuated this distortion in the gain domain. Across drugs, the groups did not differ in their probability weighting, although gamblers consistently underweighted losing probabilities in the placebo condition. Overall, our results reveal that dopamine D2/D3 receptor antagonism modulates the subjective weighting of probabilities in the gain domain, in the direction of more objective, economically rational decision making.

The Neurocognitive Cost of Enhancing Cognition with Methylphenidate: Improved Distractor Resistance but Impaired Updating.

A balance has to be struck between supporting distractor-resistant representations in working memory and allowing those representations to be updated. Catecholamine, particularly dopamine, transmission has been proposed to modulate the balance between the stability and flexibility of working memory representations. However, it is unclear whether drugs that increase catecholamine transmission, such as methylphenidate, optimize this balance in a task-dependent manner or bias the system toward stability at the expense of flexibility (or vice versa). Here we demonstrate, using pharmacological fMRI, that methylphenidate improves the ability to resist distraction (cognitive stability) but impairs the ability to flexibly update items currently held in working memory (cognitive flexibility). These behavioral effects were accompanied by task-general effects in the striatum and opposite and task-specific effects on neural signal in the pFC. This suggests that methylphenidate exerts its cognitive enhancing and impairing effects through acting on the pFC, an effect likely associated with methylphenidate's action on the striatum. These findings highlight that methylphenidate acts as a double-edged sword, improving one cognitive function at the expense of another, while also elucidating the neurocognitive mechanisms underlying these paradoxical effects.

Neuronal Oscillations with Non-sinusoidal Morphology Produce Spurious Phase-to-Amplitude Coupling and Directionality.

Neuronal oscillations support cognitive processing. Modern views suggest that neuronal oscillations do not only reflect coordinated activity in spatially distributed networks, but also that there is interaction between the oscillations at different frequencies. For example, invasive recordings in animals and humans have found that the amplitude of fast oscillations (>40 Hz) occur non-uniformly within the phase of slower oscillations, forming the so-called cross-frequency coupling (CFC). However, the CFC patterns might be influenced by features in the signal that do not relate to underlying physiological interactions. For example, CFC estimates may be sensitive to spectral correlations due to non-sinusoidal properties of the alpha band wave morphology. To investigate this issue, we performed CFC analysis using experimental and synthetic data. The former consisted in a double-blind magnetoencephalography pharmacological study in which participants received either placebo, 0.5 or 1.5 mg of lorazepam (LZP; GABAergic enhancer) in different experimental sessions. By recording oscillatory brain activity with during rest and working memory (WM), we were able to demonstrate that posterior alpha (8-12 Hz) phase was coupled to beta-low gamma band (20-45 Hz) amplitude envelope during all sessions. Importantly, bicoherence values around the harmonics of the alpha frequency were similar both in magnitude and topographic distribution to the cross-frequency coherence (CFCoh) values observed in the alpha-phase to beta-low gamma coupling. In addition, despite the large CFCoh we found no significant cross-frequency directionality (CFD). Critically, simulations demonstrated that a sizable part of our empirical CFCoh between alpha and beta-low gamma coupling and the lack of CFD could be explained by two-three harmonics aligned in zero phase-lag produced by the physiologically characteristic alpha asymmetry in the amplitude of the peaks relative to the troughs. Furthermore, we showed that periodic signals whose waveform deviate from pure sine waves produce non-zero CFCoh with predictable CFD. Our results reveal the important role of the non-sinusoidal wave morphology on state of the art CFC metrics and we recommend caution with strong physiological interpretations of CFC and suggest basic data quality checks to enhance the mechanistic understanding of CFC.

Posterior alpha oscillations reflect attentional problems in boys with Attention Deficit Hyperactivity Disorder.

OBJECTIVE: This study aimed to characterize alpha modulations in children with ADHD in relation to their attentional performance. METHODS: The posterior alpha activity (8-12Hz) was measured in 30 typically developing children and 30 children with ADHD aged 7-10years, using EEG while they performed a visuospatial covert attention task. We focused the analyses on typically developing boys (N=9) and boys with ADHD (N=17). RESULTS: Alpha activity in typically developing boys was similar to previous results of healthy adults: it decreased in the hemisphere contralateral to the attended hemifield, whereas it relatively increased in the other hemisphere. However, in boys with ADHD this hemispheric lateralization in the alpha band was not obvious (group contrast, p=.018). A robust relation with behavioral performance was lacking in both groups. CONCLUSIONS: The ability to modulate alpha oscillations in visual regions with the allocation of spatial attention was clearly present in typically developing boys, but not in boys with ADHD. SIGNIFICANCE: These results open up the possibility to further study the underlying mechanisms of ADHD by examining how differences in the fronto-striatal network might explain different abilities in modulating the alpha band activity.

Amplified Striatal Responses to Near-Miss Outcomes in Pathological Gamblers.

Near-misses in gambling games are losing events that come close to a win. Near-misses were previously shown to recruit reward-related brain regions including the ventral striatum, and to invigorate gambling behavior, supposedly by fostering an illusion of control. Given that pathological gamblers are particularly vulnerable to such cognitive illusions, their persistent gambling behavior might result from an amplified striatal sensitivity to near-misses. In addition, animal studies have shown that behavioral responses to near-miss-like events are sensitive to dopamine, but this dopaminergic influence has not been tested in humans. To investigate these hypotheses, we recruited 22 pathological gamblers and 22 healthy controls who played a slot machine task delivering wins, near-misses and full-misses, inside an fMRI scanner. Each participant played the task twice, once under placebo and once under a dopamine D2 receptor antagonist (sulpiride 400 mg), in a double-blind, counter-balanced design. Participants were asked about their motivation to continue gambling throughout the task. Across all participants, near-misses elicited higher motivation to continue gambling and increased striatal responses compared with full-misses. Crucially, pathological gamblers showed amplified striatal responses to near-misses compared with controls. These group differences were not observed following win outcomes. In contrast to our hypothesis, sulpiride did not induce any reliable modulation of brain responses to near-misses. Together, our results demonstrate that pathological gamblers have amplified brain responses to near-misses, which likely contribute to their persistent gambling behavior. However, there is no evidence that these responses are influenced by dopamine. These results have implications for treatment and gambling regulation.

Methylphenidate alters selective attention by amplifying salience.

RATIONALE: Methylphenidate, the most common treatment of attention deficit hyperactivity disorder (ADHD), is increasingly used by healthy individuals as a "smart drug" to enhance cognitive abilities like attention. A key feature of (selective) attention is the ability to ignore irrelevant but salient information in the environment (distractors). Although crucial for cognitive performance, until now, it is not known how the use of methylphenidate affects resistance to attentional capture by distractors. OBJECTIVES: The present study aims to clarify how methylphenidate affects distractor suppression in healthy individuals. METHODS: The effect of methylphenidate (20 mg) on distractor suppression was assessed in healthy subjects (N = 20), in a within-subject double-blind placebo-controlled crossover design. We used a visuospatial attention task with target faces flanked by strong (faces) or weak distractors (scrambled faces). RESULTS: Methylphenidate increased accuracy on trials that required gender identification of target face stimuli (methylphenidate 88.9 ± 1.4 [mean ± SEM], placebo 86.0 ± 1.2 %; p = .003), suggesting increased processing of the faces. At the same time, however, methylphenidate increased reaction time when the target face was flanked by a face distractor relative to a scrambled face distractor (methylphenidate 34.9 ± 3.73, placebo 26.7 ± 2.84 ms; p = .027), suggesting enhanced attentional capture by distractors with task-relevant features. CONCLUSIONS: We conclude that methylphenidate amplifies salience of task-relevant information at the level of the stimulus category. This leads to enhanced processing of the target (faces) but also increased attentional capture by distractors drawn from the same category as the target.

Lateralized modulation of posterior alpha oscillations in children.

The evidence for a functionally inhibitory role of alpha oscillations is growing stronger, mostly derived from studies in healthy adults investigating spatial attention. It remains unexplored if the modulation of alpha band oscillations plays a similar functional role in typically developing children. The aim of this study was to characterize alpha modulations in children in relation to attentional performance. To this end, the posterior alpha activity (8-12Hz) in children between 7 and 10years old was measured using EEG while they performed a visuospatial covert attention task. We found that the alpha activity decreased in the hemisphere contralateral to the attended hemifield, whereas it relatively increased in the other hemisphere. In addition, we found that the degree of lateralized alpha modulation predicted performance on the attention task by negatively predicting the response time on invalid trials. Of note, children who were behaviorally less influenced by spatial cueing also were children with a clear lateralized alpha modulation pattern, with a significantly stronger alpha lateralization in the left hemisphere than children who were influenced more by spatial cueing. In addition, a bias to the right visual field such as that commonly observed in children, was significantly smaller or absent in the children influenced least by spatial cueing. Among all children, the magnitude of this visual field bias was positively related to the ability to modulate alpha activity. In conclusion, we have shown that the pattern of alpha oscillations modulated by attention is already present in 7-10year old typically developing children. Although a similar pattern is observed in adults, the consequences for behavior are different. The fact that alpha modulation is already present at this age opens up the possibility of using hemispheric alpha lateralization as a tool to study the physiological basis of attention deficits in clinical disorders such as ADHD.

Abnormal modulation of reward versus punishment learning by a dopamine D2-receptor antagonist in pathological gamblers.

RATIONALE: Pathological gambling has been associated with dopamine transmission abnormalities, in particular dopamine D2-receptor deficiency, and reversal learning deficits. Moreover, pervasive theoretical accounts suggest a key role for dopamine in reversal learning. However, there is no empirical evidence for a direct link between dopamine, reversal learning and pathological gambling. OBJECTIVE: The aim of the present study is to triangulate dopamine, reversal learning, and pathological gambling. METHODS: Here, we assess the hypothesis that pathological gambling is accompanied by dopamine-related problems with learning from reward and punishment by investigating effects of the dopamine D2-receptor antagonist sulpiride (400 mg) on reward- and punishment-based reversal learning in 18 pathological gamblers and 22 healthy controls, using a placebo-controlled, double-blind, counter-balanced design. RESULTS: In line with previous studies, blockade of D2 receptors with sulpiride impaired reward versus punishment reversal learning in controls. By contrast, sulpiride did not have any outcome-specific effects in gamblers. CONCLUSION: These data demonstrate that pathological gambling is associated with a dopamine-related anomaly in reversal learning from reward and punishment.

GABAergic modulation of visual gamma and alpha oscillations and its consequences for working memory performance.

BACKGROUND: Impressive in vitro research in rodents and computational modeling has uncovered the core mechanisms responsible for generating neuronal oscillations. In particular, GABAergic interneurons play a crucial role for synchronizing neural populations. Do these mechanistic principles apply to human oscillations associated with function? To address this, we recorded ongoing brain activity using magnetoencephalography (MEG) in healthy human subjects participating in a double-blind pharmacological study receiving placebo, 0.5 mg and 1.5 mg of lorazepam (LZP; a benzodiazepine upregulating GABAergic conductance). Participants performed a demanding visuospatial working memory (WM) task. RESULTS: We found that occipital gamma power associated with WM recognition increased with LZP dosage. Importantly, the frequency of the gamma activity decreased with dosage, as predicted by models derived from the rat hippocampus. A regionally specific gamma increase correlated with the drug-related performance decrease. Despite the system-wide pharmacological intervention, gamma power drug modulations were specific to visual cortex: sensorimotor gamma power and frequency during button presses remained unaffected. In contrast, occipital alpha power modulations during the delay interval decreased parametrically with drug dosage, predicting performance impairment. Consistent with alpha oscillations reflecting functional inhibition, LZP affected alpha power strongly in early visual regions not required for the task demonstrating a regional specific occipital impairment. CONCLUSIONS: GABAergic interneurons are strongly implicated in the generation of gamma and alpha oscillations in human occipital cortex where drug-induced power modulations predicted WM performance. Our findings bring us an important step closer to linking neuronal dynamics to behavior by embracing established animal models.

Working memory capacity predicts effects of methylphenidate on reversal learning.

Increased use of stimulant medication, such as methylphenidate, by healthy college students has raised questions about its cognitive-enhancing effects. Methylphenidate acts by increasing extracellular catecholamine levels and is generally accepted to remediate cognitive and reward deficits in patients with attention deficit hyperactivity disorder. However, the cognitive-enhancing effects of such 'smart drugs' in the healthy population are still unclear. Here, we investigated effects of methylphenidate (Ritalin, 20 mg) on reward and punishment learning in healthy students (N=19) in a within-subject, double-blind, placebo-controlled cross-over design. Results revealed that methylphenidate effects varied both as a function of task demands and as a function of baseline working memory capacity. Specifically, methylphenidate improved reward vs punishment learning in high-working memory subjects, whereas it impaired reward vs punishment learning in low-working memory subjects. These results contribute to our understanding of individual differences in the cognitive-enhancing effects of methylphenidate in the healthy population. Moreover, they highlight the importance of taking into account both inter- and intra-individual differences in dopaminergic drug research.

Behavioral consequences of aberrant alpha lateralization in attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by problems in directing and sustaining attention. Recent findings suggest that alpha oscillations (8-12 Hz) are crucially involved in gating information between brain regions when allocating attention. The current study investigates whether aberrant modulation of alpha oscillations contributes to attention problems in ADHD patients. METHODS: Magnetoencephalographic signals were recorded in adults with ADHD (n = 17) and healthy control subjects (n = 18) while they performed a visuospatial attention task. Cues directed attention to the left or right visual hemifield with an 80% validity with respect to the upcoming target. RESULTS: Unlike the control group, subjects with ADHD showed a higher accuracy for invalidly cued right targets compared with invalidly cued left targets (p = .04). This coincided with an inability of the ADHD subjects to sustain the posterior hemispheric alpha lateralization in the period before the target for the left cue condition (p = .011). Furthermore, the control group showed a strong correlation between the degree of alpha lateralization and the magnitude of the cueing effect assessed in terms of accuracy (rs = .71, p = .001) and reaction times (rs =-.81, p<.001). These correlations were absent in the ADHD group. CONCLUSIONS: Our results demonstrate that subjects with ADHD have a failure in sustaining hemispheric alpha lateralization when cued to the left, resulting in an attentional bias to the right visual hemifield. These findings suggest that aberrant modulations of alpha oscillations reflect attention problems in ADHD and might be related to the neurophysiological substrate of the disorder.

Parieto-occipital sources account for the increase in alpha activity with working memory load.

The role of oscillatory alpha activity (8-13 Hz) in cognitive processing remains an open question. It has been debated whether alpha activity plays a direct role in the neuronal processing required for a given task or whether it reflects idling and/or functional inhibition. Recent electroencephalography (EEG) studies have demonstrated that alpha activity increases parametrically with load during retention in working memory paradigms. While it is known that the parieto-occipital cortex is involved in the generation of the spontaneous alpha oscillations, it remains unknown where the sources of the memory-dependent alpha activity are located. We recorded brain activity using magnetoencephalography (MEG) from human subjects performing a Sternberg memory task where faces were used as stimuli. Spectral analysis revealed a parametric increase in alpha activity with memory load over posterior brain areas. We then applied a source reconstruction technique that allowed us to map the parametric increase in alpha activity to the anatomical magnetic resonance (MR) images of the subject. The primary sources of the memory-dependent alpha activity were in the vicinity of the parieto-occipital sulcus. This region is not directly involved in working memory maintenance of faces. Our findings are consistent with the notion that alpha activity reflects disengagement or inhibition of the visual dorsal stream. We propose that the disengagement reflected in alpha power serves to suppress visual input in order to devote resources to structures responsible for working memory maintenance.