Examining the role of dopamine in methylphenidate's effects on resting brain function.

The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.

Seasonality in regional brain glucose metabolism.

BACKGROUND: Daylength and the rates of changes in daylength have been associated with seasonal fluctuations in psychiatric symptoms and in cognition and mood in healthy adults. However, variations in human brain glucose metabolism in concordance with seasonal changes remain under explored. METHODS: In this cross-sectional study, we examined seasonal effects on brain glucose metabolism, which we measured using 18F-fluorodeoxyglucose-PET in 97 healthy participants. To maximize the sensitivity of regional effects, we computed relative metabolic measures by normalizing the regional measures to white matter metabolism. Additionally, we explored the role of rest-activity rhythms/sleep-wake activity measured with actigraphy in the seasonal variations of regional brain metabolic activity. RESULTS: We found that seasonal variations of cerebral glucose metabolism differed across brain regions. Glucose metabolism in prefrontal regions increased with longer daylength and with greater day-to-day increases in daylength. The cuneus and olfactory bulb had the maximum and minimum metabolic values around the summer and winter solstice respectively (positively associated with daylength), whereas the temporal lobe, brainstem, and postcentral cortex showed maximum and minimum metabolic values around the spring and autumn equinoxes, respectively (positively associated with faster daylength gain). Longer daylength was associated with greater amplitude and robustness of diurnal activity rhythms suggesting circadian involvement. CONCLUSIONS: The current findings advance our knowledge of seasonal patterns in a key indicator of brain function relevant for mood and cognition. These data could inform treatment interventions for psychiatric symptoms that peak at specific times of the year.

Activation of brain arousal networks coincident with eye blinks during resting state.

Eye-blinking has been implicated in arousal and attention. Here we test the hypothesis that blinking-moments represent arousal surges associated with activation of the ascending arousal network (AAN) and its thalamic projections. For this purpose, we explored the temporal relationship between eye-blinks and fMRI BOLD activity in AAN and thalamic nuclei, as well as whole brain cluster corrected activations during eyes-open, resting-state fMRI scanning. We show that BOLD activations in the AAN nuclei peaked prior to the eye blinks and in thalamic nuclei peaked prior to and during the blink, consistent with the role of eye blinking in arousal surges. Additionally, we showed visual cortex peak activation prior to the eye blinks, providing further evidence of the visual cortex's role in arousal, and document cerebellar peak activation post eye blinks, which might reflect downstream engagement from arousal surges.

Relationship between BMI and alcohol consumption levels in decision making.

BACKGROUND: Decision-making deficits in obesity and alcohol use disorder (AUD) may contribute to the choice of immediate rewards despite their long-term deleterious consequences. METHODS: Gambling task functional MRI in Human connectome project (HCP) dataset was used to investigate neural activation differences associated with reward or punishment (a key component of decision-making behavior) in 418 individuals with obesity (high BMI) and without obesity (lean BMI) and either at high (HR) or low (LR) risk of AUD based on their alcohol drinking levels. RESULTS: Interaction between BMI and alcohol drinking was seen in regions of the default mode network (DMN) and those implicated in self-related processing, memory, and salience attribution. ObesityHR relative to obesityLR also recruited DMN along with primary motor and regions implicated in inattention, negative perception, and uncertain choices, which might facilitate impulsive choices in obesityHR. Furthermore, obesityHR compared to leanHR/leanLR also demonstrated heightened activation in DMN and regions implicated in uncertain decisions. CONCLUSIONS: These results suggest that BMI is an independent variable from that of alcohol drinking levels in neural processing of gambling tasks. Moreover, leanLR relative to leanHR, showed increased activation in motor regions [precentral and superior frontal gyrus] suggestive of worse executive function from excessive alcohol use. Delayed discounting measures failed to distinguish between obesity and high alcohol drinking levels, which as for gambling task results suggests independent negative effects of obesity and chronic alcohol drinking on decision-making. These findings highlight distinct associations of obesity and high-risk alcohol drinking with two key constituents of decision-making behavior.

Apparent diffusion coefficient changes in human brain during sleep - Does it inform on the existence of a glymphatic system?

The role of sleep in brain physiology is poorly understood. Recently rodent studies have shown that the glymphatic system clears waste products from brain more efficiently during sleep compared to wakefulness due to the expansion of the interstitial fluid space facilitating entry of cerebrospinal fluid (CSF) into the brain. Here, we studied water diffusivity in the brain during sleep and awake conditions, hypothesizing that an increase in water diffusivity during sleep would occur concomitantly with an expansion of CSF volume - an effect that we predicted based on preclinical findings would be most prominent in cerebellum. We used MRI to measure slow and fast components of the apparent diffusion coefficient (ADC) of water in the brain in 50 healthy participants, in 30 of whom we compared awake versus sleep conditions and in 20 of whom we compared rested-wakefulness versus wakefulness following one night of sleep-deprivation. Sleep compared to wakefulness was associated with increases in slow-ADC in cerebellum and left temporal pole and with decreases in fast-ADC in thalamus, insula, parahippocampus and striatal regions, and the density of sleep arousals was inversely associated with ADC changes. The CSF volume was also increased during sleep and was associated with sleep-induced changes in ADCs in cerebellum. There were no differences in ADCs with wakefulness following sleep deprivation compared to rested-wakefulness. Although we hypothesized increases in ADC with sleep, our findings uncovered both increases in slow ADC (mostly in cerebellum) as well as decreases in fast ADC, which could reflect the distinct biological significance of fast- and slow-ADC values in relation to sleep. While preliminary, our findings suggest a more complex sleep-related glymphatic function in the human brain compared to rodents. On the other hand, our findings of sleep-induced changes in CSF volume provide preliminary evidence that is consistent with a glymphatic transport process in the human brain.

Blink-induced changes in pupil dynamics are consistent and heritable.

Pupil size and blink rates are heritable but the extent to which they interact with one another has not been properly investigated. Though changes in pupil size due to eye blinks have been reported, they are considered a pupillary artifact. In this study we used the HCP 7T fMRI dataset with resting state eye-tracking data obtained in monozygous and dizygous twins to assess their heritability and their interactions. For this purpose, we characterized the pupil dilation (positive peak) and constriction (negative peak) that followed blink events, which we describe as blink-induced pupillary response (BIPR). We show that the BIPR is highly consistent with a positive dilatory peak (D-peak) around 500ms and a negative constricting peak (C-peak) around 1s. These patterns were reproducible within- and between- subjects across two time points and differed by vigilance state (vigilant versus drowsy). By comparing BIPR between monozygous and dizygous twins we show that BIPR have a heritable component with significant additive genetic (A) and environmental (E) factors dominating the structural equation models, particularly in the time-domain for both D- and C-peaks and amplitude domain for the C-peak. (a2 between 42-49%). Blink duration, pupil size and blink rate were also found to be highly heritable (a2 up to 62% for pupil size). Our study documents an association between BIPR and wakefulness and indicates that BIPR should not be treated as a coincidental artefact, but part of a larger oculomotor system that we label here as Oculomotor Adaptive System, OAS, that is genetically determined.

Sleep deprivation effects on brain state dynamics are associated with dopamine D2 receptor availability via network control theory.

BACKGROUND: Sleep deprivation (SD) negatively affects brain function. Most brain imaging studies have investigated the effects of SD on 'static' brain function. SD effects on functional brain dynamics and their relationship with molecular changes remain relatively unexplored. METHODS: We used functional MRI to examine resting brain state dynamics after one night of SD compared to rested wakefulness (RW) and assessed their association with striatal brain dopamine D2 receptor availability (D2R) measured by PET-[11C]raclopride using network control theory. RESULTS: SD reduced dwell time and persistence probabilities with the strongest effects in two brain states, one characterized by high default mode network and low dorsal attention network activity and the other by high frontal parietal network and low somatomotor network activity. Using network control theory, we showed that after SD there was an overall increase in the control energy required for brain state transitions with effects varying for different brain state transitions. Control energy requirement was negatively associated with transition probabilities under SD and RW and accounted for SD-induced changes in transition probabilities. Alteration in the energy landscape was associated with SD-induced changes in striatal D2R distribution. CONCLUSIONS: These findings demonstrate altered occurrence of internally and externally oriented brain states following acute SD and suggest an association with energy requirements for brain state transitions modulated by striatal D2R.

Disrupted brain state dynamics in opioid and alcohol use disorder: attenuation by nicotine use.

Substance use disorder (SUD) is a chronic relapsing disorder with long-lasting changes in brain intrinsic networks. While most research to date has focused on static functional connectivity, less is known about the effect of chronic drug use on dynamics of brain networks. Here we investigated brain state dynamics in individuals with opioid use (OUD) and alcohol use disorder (AUD) and assessed how concomitant nicotine use, which is frequent among individuals with OUD and AUD, affects brain dynamics. Resting-state functional magnetic resonance imaging data of 27 OUD, 107 AUD, and 137 healthy participants were included in the analyses. To identify recurrent brain states and their dynamics, we applied a data-driven clustering approach that determines brain states at a single time frame. We found that OUD and AUD non-smokers displayed similar changes in brain state dynamics including decreased fractional occupancy or dwell time in default mode network (DMN)-dominated brain states and increased appearance rate in visual network (VIS)-dominated brain states, which were also reflected in transition probabilities of related brain states. Interestingly, co-use of nicotine affected brain states in an opposite manner by lowering VIS-dominated and enhancing DMN-dominated brain states in both OUD and AUD participants. Our finding revealed a similar pattern of brain state dynamics in OUD and AUD participants that differed from controls, with an opposite effect for nicotine use suggesting distinct effects of various drugs on brain state dynamics. Different strategies for treating SUD may need to be implemented based on patterns of co-morbid drug use.

Cortical D1 and D2 dopamine receptor availability modulate methylphenidate-induced changes in brain activity and functional connectivity.

Dopamine signaling plays a critical role in shaping brain functional network organization and behavior. Prominent theories suggest the relative expression of D1- to D2-like dopamine receptors shapes excitatory versus inhibitory signaling, with broad consequences for cognition. Yet it remains unknown how the balance between cortical D1R versus D2R signaling coordinates the activity and connectivity of functional networks in the human brain. To address this, we collected three PET scans and two fMRI scans in 36 healthy adults (13 female/23 male; average age 43 ± 12 years), including a baseline D1R PET scan and two sets of D2R PET scans and fMRI scans following administration of either 60 mg oral methylphenidate or placebo (two separate days, blinded, order counterbalanced). The drug challenge allowed us to assess how pharmacologically boosting dopamine levels alters network organization and behavior in association with D1R-D2R ratios across the brain. We found that the relative D1R-D2R ratio was significantly greater in high-level association cortices than in sensorimotor cortices. After stimulation with methylphenidate compared to placebo, brain activity (as indexed by the fractional amplitude of low frequency fluctuations) increased in association cortices and decreased in sensorimotor cortices. Further, within-network resting state functional connectivity strength decreased more in sensorimotor than association cortices following methylphenidate. Finally, in association but not sensorimotor cortices, the relative D1R-D2R ratio (but not the relative availability of D1R or D2R alone) was positively correlated with spatial working memory performance, and negatively correlated with age. Together, these data provide a framework for how dopamine-boosting drugs like methylphenidate alter brain function, whereby regions with relatively higher inhibitory D2R (i.e., sensorimotor cortices) tend to have greater decreases in brain activity and connectivity compared to regions with relatively higher excitatory D1R (i.e., association cortices). They also support the importance of a balanced interaction between D1R and D2R in association cortices for cognitive function and its degradation with aging.

Conscious and unconscious brain responses to food and cocaine cues.

Visual presentation of appetitive and negative cues triggers fast responses in the human brain. Here we assessed functional MRI (fMRI) responses to food, cocaine, and neutral cues presented at a subliminal ("unconscious", 33 ms) and supraliminal ("conscious", 750 and 3000 ms) level in healthy, cocaine naïve volunteers. Because there is evidence of circadian variability in reward sensitivity, our second aim was to assess diurnal variability in the brain's reactivity to cues. Sixteen participants completed two randomly ordered fMRI sessions (once 9-11 AM and another 5-7 PM). in which food, cocaine, and neutral cues were presented for 33, 750 and 3000 ms. Participants rated food cues as positive and "wanted" (more so in evenings than mornings), and cocaine cues as negative (no diurnal differences). fMRI showed occipital cortex activation for food>neutral, cocaine>neutral and cocaine>food; dorsolateral prefrontal cortex for cocaine>neutral and cocaine>food, and midbrain for cocaine>food (all pFWE < 0.05). When comparing unconscious (33 ms) > conscious (750 and 3000 ms) presentations, we observed significant differences for cocaine>neutral and cocaine>food in occipital cortex, for cocaine>neutral in the insula/temporal lobe, and for food>neutral in the middle temporal gyrus (pFWE < 0.05). No diurnal differences for brain activations were observed. We interpret these findings to suggest that negative items (e.g., cocaine) might be perceived at a faster speed than positive ones (e.g., food), although we cannot rule out that the higher saliency of cocaine cues, which would be novel to non-drug using individuals, contributed to the faster speed of detection.

Methylphenidate's effects on thalamic metabolism and functional connectivity in cannabis abusers and healthy controls.

Methylphenidate (MPH) is a first line treatment for ADHD and is also misused as a purported cognitive enhancer, yet its effects on brain function are still poorly understood. Recent functional magnetic resonance imaging (fMRI) studies showed that MPH altered cortico-striatal resting functional connectivity (RFC). Here we investigated the effects of MPH in thalamic connectivity since the thalamus modulates striato-cortical signaling. We hypothesized that MPH would increase thalamic connectivity and metabolism, and that this response would be blunted in cannabis abusers. For this purpose, we measured RFC in seven thalamic nuclei using fMRI and brain glucose metabolism using positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG) in sixteen healthy controls and thirteen participants with cannabis use disorder (CUD) twice after placebo and after MPH (0.5 mg/kg, iv). MPH significantly increased thalamo-cerebellar connectivity and cerebellar metabolism to the same extent in both groups. Group comparisons revealed that in CUD compared to controls, metabolism in nucleus accumbens was lower for the placebo and MPH measures, that MPH-induced increases in thalamic metabolism were blunted, and that enhanced negative connectivity between thalamus and accumbens in CUD was normalized by MPH (reducing negative connectivity). Our findings identify the thalamus as a target of MPH, which increased its metabolism and connectivity. The reduced metabolism in nucleus accumbens and the disrupted thalamo-accumbens connectivity (enhanced negative connectivity) in CUD is consistent with impaired reactivity of the brain reward's circuit. MPH's normalization of thalamo-accumbens connectivity (reduced negative connectivity) brings forth its potential therapeutic value in CUD, which merits investigation.

On the universality of language comprehension strategies: evidence from Turkish.

A fundamental question in psycholinguistic research concerns the universality of comprehension strategies. We investigated this issue by examining the so-called "subject preference" in Turkish, a language which allows for a natural (unmarked) object reading of an initial ambiguous argument. Using event-related brain potentials (ERPs), we observed increased processing difficulty in the form of a broadly distributed positivity when an initial ambiguous argument was disambiguated towards an object reading. This effect was independent of the animacy (i.e. semantic subject prototypicality) of the ambiguous argument. Our results therefore speak in favour of a universal tendency to interpret the first argument encountered as the "subject" of the clause, even in languages providing no obvious structural motivation for such a strategy. However, we argue that the underlying explanation for this preference must be modified in accordance with cross-linguistic considerations.

Genetic influences on functional connectivity associated with feedback processing and prediction error: Phase coupling of theta-band oscillations in twins.

Detection and evaluation of the mismatch between the intended and actually obtained result of an action (reward prediction error) is an integral component of adaptive self-regulation of behavior. Extensive human and animal research has shown that evaluation of action outcome is supported by a distributed network of brain regions in which the anterior cingulate cortex (ACC) plays a central role, and the integration of distant brain regions into a unified feedback-processing network is enabled by long-range phase synchronization of cortical oscillations in the theta band. Neural correlates of feedback processing are associated with individual differences in normal and abnormal behavior, however, little is known about the role of genetic factors in the cerebral mechanisms of feedback processing. Here we examined genetic influences on functional cortical connectivity related to prediction error in young adult twins (age 18, n=399) using event-related EEG phase coherence analysis in a monetary gambling task. To identify prediction error-specific connectivity pattern, we compared responses to loss and gain feedback. Monetary loss produced a significant increase of theta-band synchronization between the frontal midline region and widespread areas of the scalp, particularly parietal areas, whereas gain resulted in increased synchrony primarily within the posterior regions. Genetic analyses showed significant heritability of frontoparietal theta phase synchronization (24 to 46%), suggesting that individual differences in large-scale network dynamics are under substantial genetic control. We conclude that theta-band synchronization of brain oscillations related to negative feedback reflects genetically transmitted differences in the neural mechanisms of feedback processing. To our knowledge, this is the first evidence for genetic influences on task-related functional brain connectivity assessed using direct real-time measures of neuronal synchronization.

Neural correlates of verbal joint action: ERPs reveal common perception and action systems in a shared-Stroop task.

Recent social-cognitive research suggests that the anticipation of co-actors' actions influences people's mental representations. However, the precise nature of such representations is still unclear. In this study we investigated verbal joint representations in a delayed Stroop paradigm, where each participant responded to one color after a short delay. Participants either performed the task as a single actor (single-action, Experiment 1), or they performed it together (joint-action, Experiment 2). We investigated effects of co-actors' actions on the ERP components associated with perceptual conflict (Go N2) and response selection (P3b). Compared to single-action, joint-action reduced the N2 amplitude congruency effect when participants had to respond (Go trials), indicating that representing a co-actor's utterance helped to dissociate action codes and attenuated perceptual conflict for the responding participant. Yet, on NoGo trials the centro-parietal P3 (P3b) component amplitude increased for joint-action, suggesting that participants mapped the stimuli onto the co-actor's upcoming response as if it were their own response. We conclude that people represent others' utterances similarly to the way they represent their own utterances, and that shared perception-action codes for self and others can sometimes reduce, rather than enhance, perceptual conflict.

ERP correlates of spatially incongruent object identification during scene viewing: contextual expectancy versus simultaneous processing.

Object processing is affected by the gist of the scene within which it is embedded. Previous ERP research has suggested that manipulating the semantic congruency between an object and the surrounding scene affects the high level (semantic) representation of that object emerging after the presentation of the scene (Ganis & Kutas, 2003). In two ERP experiments, we investigated whether there would be a similar electrophysiological response when spatial congruency of an object in a scene was manipulated while the semantic congruency remained the same. Apart from the location of the object, all other object features were congruent with the scene (e.g., in a bedroom scene, either a painting or a cat appeared on the wall). In the first experiment, participants were shown a location cue and then a scene image for 300 ms, after which an object image appeared on the cued location for 300 ms. Spatially incongruent objects elicited a stronger centro-frontal N300-N400 effect in the 275-500 ms window relative to the spatially congruent objects. We also found early ERP effects, dominant on the left hemisphere electrodes. Strikingly, LORETA analysis revealed that these activations were mainly located in the superior and middle temporal gyrus of the right hemisphere. In the second experiment, we used a paradigm similar to Mudrik, Lamy, and Deouell (2010). The scene and the object were presented together for 300 ms after the location cue. This time, we did not observe either an early or the pronounced N300-N400 effect. In contrast to Experiment 1, LORETA analysis on the N400 time-window revealed that the generators of these weak ERP effects were mainly located in the temporal lobe of the left hemisphere. Our results suggest that, when the scene is presented before the object, top-down spatial encoding processes are initiated and the right superior temporal gyrus is activated, as previously suggested (Ellison, Schindler, Pattison, & Milner, 2004). Mismatch between the actual object features and the spatially driven top-down structural and functional features could lead to the early effect, and then to the N300-N400 effect. In contrast, when the scene is not presented before the object, the spatial encoding could not happen early and strong enough to initiate spatial object-integration effects. Our results indicate that spatial information is an early and essential part in scene-object integration, and it primes structural as well as semantic features of an object.