fMRI identifies chronotype-specific brain activation associated with attention to motion--why we need to know when subjects go to bed.

Human cognition relies on attentional capacities which, among others, are influenced by factors like tiredness or mood. Based on their inherent preferences in sleep and wakefulness, individuals can be classified as specific "chronotypes". The present study investigated how early, intermediate and late chronotypes (EC, IC, LC) differ neurally on an attention-to-motion task. Twelve EC, 18 IC and 17 LC were included into the study. While undergoing functional magnetic resonance imaging (fMRI) scans, subjects looked at vertical bars in an attention-to-motion task. In the STATIONARY condition, subjects focused on a central fixation cross. During Fix-MOVING and Attend-MOVING, bars were moving horizontally. Only during the Attend-MOVING, subjects were required to attend to changes in the velocity of bars and indicate those by button presses. A two-way repeated measures ANOVA probed group by attentional load effects. The dorsolateral prefrontal cortex (DLPFC), insula and anterior cingulate cortex showed group by attention specific activations. Specifically, EC and LC presented attenuated DLPFC activation under high attentional load (Attend-MOVING), while EC showed less anterior insula activation than IC. LC compared to IC exhibited attenuation of superior parietal cortex. Our study reveals that individual sleep preferences are associated with characteristic brain activation in areas crucial for attention and bodily awareness. These results imply that considering sleep preferences in neuroimaging studies is crucial when administering cognitive tasks. Our study also has socio-economic implications. Task performance in non-optimal times of the day (e.g. shift workers), may result in cognitive impairments leading to e.g. increased error rates and slower reaction times.

"Early to bed, early to rise": diffusion tensor imaging identifies chronotype-specificity.

Sleep and wakefulness are crucial prerequisites for cognitive efficiency, the disturbances of which severely impact performance and mood as present e.g. after time zone traveling, in shift workers or patients with sleep or affective disorders. Based on their individual disposition to sleep and wakefulness, humans can be categorized as early (EC), late (LC) or intermediate (IC) chronotypes. While ECs tend to wake up early in the morning and find it difficult to remain awake beyond their usual bedtime, LCs go to bed late and have difficulties getting up. Beyond sleep/wake timings, chronotypes show distinct patterns of cognitive performance, gene expression, endocrinology and lifestyle. However, little is known about brain structural characteristics potentially underlying differences. Specifically, white matter (WM) integrity is crucial for intact brain function and has been related to various lifestyle habits, suggesting differences between chronotypes. Hence, the present study draws on Diffusion Tensor Imaging as a powerful tool to non-invasively probe WM architecture in 16 ECs, 23 LCs and 20 ICs. Track-based spatial statistics highlight that LCs were characterized by WM differences in the frontal and temporal lobes, cingulate gyrus and corpus callosum. Results are discussed in terms of findings reporting late chronotypes to exhibit a chronic form of jet lag accompanied with sleep disturbances, vulnerability to depression and higher consumption of nicotine and alcohol. This study has far-reaching implications for health and the economy. Ideally, work schedules should fit in with chronotype-specificity whenever possible.

Do EEG paradigms work in fMRI? Varying task demands in the visual oddball paradigm: Implications for task design and results interpretation.

We investigate the effects of variations in response requirements on BOLD activation in a visual oddball task and consider implications for fMRI task designs. Sixteen healthy subjects completed 3 runs of a visual oddball task: passive, count and respond. Besides expected activation patterns during passive viewing, we identified joint activations, but more importantly crucial differences between the count and respond versions of the task. Middle frontal gyrus activation was seen in the respond but not the count condition suggesting that this region is associated with action execution rather than the decision-making aspect of the task. In addition, activation observed in the central opercular cortex and parietal operculum in the respond (but not count) condition is likely to reflect integration of the sensory, decision and response processes. We also observed activation in the supplementary motor area (SMA) during count as well as respond. Since the count condition requires no motor planning or response our data provide evidence for an SMA involvement in decision-making. Our study clearly shows that the count and respond versions of the visual oddball task result in different patterns of BOLD activation that could both be attributed to 'target detection' if information on the respective other condition was not available. We also show that considering the elements of a complex task is crucial when transferring it from one imaging modality to another and that a motor response is not always necessary in fMRI studies when the task has been set up appropriately.

Parallel imaging acceleration of EPIK for reduced image distortions in fMRI.

EPI with Keyhole (EPIK) is a hybrid imaging technique used to improve the performance of EPI in dynamic MRI applications. The method had been previously validated at 1.5 T with both phantom and in vivo images; EPIK was able to provide a higher temporal resolution and less image distortions than single-shot EPI. The data presented here demonstrate that the performance of EPIK can be further improved by accelerating it with the parallel imaging. For this work, this combination was tested at 3 T. After initial evaluation using phantom images, use of the method in functional MRI was verified with visual fMRI measurements as well as MRI simulation results. The results showed that accelerated EPIK had increased temporal resolution with favorable robustness against susceptibility artifacts when compared with EPI or non-accelerated EPIK.

EEG acquisition in ultra-high static magnetic fields up to 9.4 T.

The simultaneous acquisition of electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) data has gained momentum in recent years due to the synergistic effects of the two modalities with regard to temporal and spatial resolution. Currently, only EEG-data recorded in fields of up to 7 T have been reported. We investigated the feasibility of recording EEG inside a 9.4 T static magnetic field, specifically to determine whether meaningful EEG information could be recovered from the data after removal of the cardiac-related artefact. EEG-data were recorded reliably and reproducibly at 9.4 T and the cardiac-related artefact increased in amplitude with increasing B0, as expected. Furthermore, we were able to correct for the cardiac-related artefact and identify auditory event related responses at 9.4 T in 75% of subjects using independent component analysis (ICA). Also by means of ICA we detected event related spectral perturbations (ERSP) in subjects at 9.4 T in response to opening/closing the eyes comparable with the response at 0 T. Overall our results suggest that it is possible to record meaningful EEG data at ultra-high magnetic fields. The simultaneous EEG-fMRI approach at ultra-high-fields opens up the horizon for investigating brain dynamics at a superb spatial resolution and a temporal resolution in the millisecond domain.

Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: evidence from fMRI in healthy subjects.

The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning.

Conflict processing networks: A directional analysis of stimulus-response compatibilities using MEG.

The suppression of distracting information in order to focus on an actual cognitive goal is a key feature of executive functions. The use of brain imaging methods to investigate the underlying neurobiological brain activations that occur during conflict processing have demonstrated a strong involvement of the fronto-parietal attention network (FPAN). Surprisingly, the directional interconnections, their time courses and activations at different frequency bands remain to be elucidated, and thus, this constitutes the focus of this study. The shared information flow between brain areas of the FPAN is provided for frequency bands ranging from the theta to the lower gamma band (4-40 Hz). We employed an adaptation of the Simon task utilizing Magnetoencephalography (MEG). Granger causality was applied to investigate interconnections between the active brain regions, as well as their directionality. Following stimulus onset, the middle frontal precentral cortex and superior parietal cortex were significantly activated during conflict processing in a time window of between 300 to 600ms. Important differences in causality were found across frequency bands between processing of conflicting stimuli in the left as compared to the right visual hemifield. The exchange of information from and to the FPAN was most prominent in the beta band. Moreover, the anterior cingulate cortex and the anterior insula represented key areas for conflict monitoring, either by receiving input from other areas of the FPAN or by generating output themselves. This indicates that the salience network is at least partly involved in processing conflict information. The present study provides detailed insights into the underlying neural mechanisms of the FPAN, especially regarding its temporal characteristics and directional interconnections.

Effects of aversive odour presentation on inhibitory control in the Stroop colour-word interference task.

BACKGROUND: Due to the unique neural projections of the olfactory system, odours have the ability to directly influence affective processes. Furthermore, it has been shown that emotional states can influence various non-emotional cognitive tasks, such as memory and planning. However, the link between emotional and cognitive processes is still not fully understood. The present study used the olfactory pathway to induce a negative emotional state in humans to investigate its effect on inhibitory control performance in a standard, single-trial manual Stroop colour-word interference task. An unpleasant (H2S) and an emotionally neutral (Eugenol) odorant were presented in two separate experimental runs, both in blocks alternating with ambient air, to 25 healthy volunteers, while they performed the cognitive task. RESULTS: Presentation of the unpleasant odorant reduced Stroop interference by reducing the reaction times for incongruent stimuli, while the presentation of the neutral odorant had no effect on task performance. CONCLUSIONS: The odour-induced negative emotional state appears to facilitate cognitive processing in the task used in the present study, possibly by increasing the amount of cognitive control that is being exerted. This stands in contrast to other findings that showed impaired cognitive performance under odour-induced negative emotional states, but is consistent with models of mood-congruent processing.

Cognitive performance and cholinergic transmission: influence of muscarinic and nicotinic receptor blockade.

The cholinergic system is essential in mediating cognitive processes. Although there has been extensive research regarding cholinergic receptor subsystems, the specific contribution of the muscarinic and nicotinic receptor system to cognitive processes still has not been sufficiently explored. In the present study, we examined the selective contribution of muscarinic and nicotinic antagonism to cognitive performance in healthy human subjects. A single-blind, double-dummy, time-elapsed, repeated measures cross-over design was used on 15 healthy males. Subjects completed a neuropsychological test battery assessing a wide range of cognitive domains after 0.4 mg scopolamine (intravenous), 0.2 mg/kg mecamylamine (max. 15 mg; oral) or placebo. Subjects were tested under three conditions: placebo/placebo (PP), scopolamine/placebo (SP) and mecamylamine/placebo (MP). Results show that scopolamine significantly impaired the free recall and recognition performance in the verbal learning test. No other cognitive domain was affected, neither by scopolamine nor by mecamylamine. In line with the existing literature, antagonism of muscarinic receptors resulted in specific cognitive impairments, predominantly memory performance.

Predicting acute affective symptoms after deep brain stimulation surgery in Parkinson's disease.

The current study aimed to investigate predictive markers for acute symptoms of depression and mania following deep brain stimulation (DBS) surgery of the subthalamic nucleus for the treatment of motor symptoms in Parkinson's disease (PD). Fourteen patients with PD (7 males) were included in a prospective longitudinal study. Neuropsychological tests, psychopathology scales and tests of motor functions were administered at several time points prior to and after neurosurgery. Pre-existing psychopathological and motor symptoms predicted postoperative affective side effects of DBS surgery. As these can easily be assessed, they should be considered along with other selection criteria for DBS surgery.

Changes in brain activation related to visuo-spatial memory after real-time fMRI neurofeedback training in healthy elderly and Alzheimer's disease.

Cognitive decline is a symptom of healthy ageing and Alzheimer's disease. We examined the effect of real-time fMRI based neurofeedback training on visuo-spatial memory and its associated neuronal response. Twelve healthy subjects and nine patients of prodromal Alzheimer's disease were included. The examination spanned five days (T1-T5): T1 contained a neuropsychological pre-test, the encoding of an itinerary and a fMRI-based task related that itinerary. T2-T4 hosted the real-time fMRI neurofeedback training of the parahippocampal gyrus and on T5 a post-test session including encoding of another itinerary and a subsequent fMRI-based task were done. Scores from neuropsychological tests, brain activation and task performance during the fMRI-paradigm were compared between pre and post-test as well as between healthy controls and patients. Behavioural performance in the fMRI-task remained unchanged, while cognitive testing showed improvements in visuo-spatial memory performance. Both groups displayed task-relevant brain activation, which decreased in the right precentral gyrus and left occipital lobe from pre to post-test in controls, but increased in the right occipital lobe, middle frontal gyrus and left frontal lobe in the patient group. While results suggest that the training has affected brain activation differently between controls and patients, there are no pointers towards a behavioural manifestation of these changes. Future research is required on the effects that can be induced using real-time fMRI based neurofeedback training and the required training duration to elicit broad and lasting effects.

Muscarinic antagonist effects on executive control of attention.

Acetylcholine plays a major role in mediating attention processes. We investigated the muscarinic antagonist effect of scopolamine on functional neuro-anatomy of attention and cognition. We assessed 12 healthy volunteers while performing the Attention Network Task on 0.4 mg scopolamine and placebo in a single-blind randomized trial in a 1.5 T magnetic resonance scanner. Neurocognitive measures included verbal learning, verbal memory, verbal fluency, trail making, digit span, a continuous performance task and a planning task (Tower of London). When compared to placebo, scopolamine increased reaction times for conflicting stimulus processing, together with decreasing brain activation in the anterior cingulate cortex (a brain region involved in conflict processing) suggestive of a muscarinic antagonist effect on executive control of attention. Contrary to the notion of a predominantly right-hemispheric lateralization of cognitive processes associated with orienting attention, scopolamine reduced brain activity in left superior and left middle frontal brain areas. Our neuropsychological test data revealed a selective effect of scopolamine on verbal learning and memory while other cognitive domains, such as planning and working memory, were unaffected. These findings are consistent with muscarinic modulation of dopaminergic neurotransmission in frontal attention networks when processing conflicting information.

Nicotinic antagonist effects on functional attention networks.

Cholinergic neurotransmission has been implicated in memory and attention. We investigated the effect of the non-competitive nicotinic antagonist mecamylamine on three components of attention processes (i.e. alerting, orienting and executive control) in 12 healthy male subjects whilst performing the Attention Network Task (ANT) in a magnetic resonance imaging (MRI) scanner. Participants received 15 mg mecamylamine in a single blind and placebo- controlled randomized procedure 90 min prior to obtaining functional MRI data. Our results confirm previous reports of beneficial effects of cueing (alerting and orienting) and detrimental effects of conflict (executive control) on reaction times when performing the ANT. The functional MRI data confirmed distinct neural networks associated with each of the three attention components. Alerting was associated with increased left temporal lobe activation while orienting increased bilateral prefrontal, right precuneus and left caudate activation. Executive control activated anterior cingulate and precuneus. Mecamylamine slowed overall response time and down-regulated brain activation associated with orienting and to some extent brain activation associated with executive control when compared to placebo. These findings are consistent with nicotinic modulation of orienting attention by cueing and executive control when responding to conflicting information. The latter nicotine antagonist effect may be mediated via cholinergic modulation of dopamine neurotransmission in mesolimbic pathways.

Differential brain activation during facial emotion discrimination in first-episode schizophrenia.

BACKGROUND: Aberrant brain activation during facial emotion discrimination has been described in chronic schizophrenia, while little is known about early stages of the illness. The aim of the current study was to investigate valence-specific brain activation of emotion discrimination in first-episode schizophrenia. These patients provide the advantage of lacking the effects of long-term medication and chronic illness course and can hence further enhance the understanding of underlying psychopathological mechanisms. METHODS: Using event-related fMRI, we investigated 18 first-episode schizophrenia patients and 18 matched healthy subjects during an explicit emotion discrimination task presenting happy, sad and neutral monochromatic facial expressions. A repeated measure analysis of variance (ANOVA) with the factors Group (patients, healthy subjects), Gender and Emotion (happy, sad, neutral) was performed on behavioural and functional data. RESULTS: Behavioural performance did not differ between groups. Valence-independent hypoactivations in patients were observed for the anterior cingulate and orbitofrontal cortex while hyperactivations emerged in the posterior cingulate and the precuneus. Emotion-specific group differences were revealed in inferior parietal and orbitofrontal brain areas and the hippocampus. CONCLUSIONS: First-episode schizophrenia already affects areas involved in processing of both, emotions and primary facial information. Our study underlines the role of dysfunctional neural networks as the basis of disturbed social interactions in early schizophrenia.

Neuregulin 1 ICE-single nucleotide polymorphism in first episode schizophrenia correlates with cerebral activation in fronto-temporal areas.

The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533) from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the at risk allele showed greater activations (P < 0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions previously associated with the pathology of Schizophrenia are differentially affected in those with a genetic at risk status in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes may be in part due to this genetic variation.

Blunted Frontostriatal Blood Oxygen Level-Dependent Signals Predict Stimulant and Marijuana Use.

BACKGROUND: Occasional recreational stimulant (amphetamine and cocaine) use is an important public health problem among young adults because 16% of those who experiment develop stimulant use disorder. This study aimed to determine whether behavioral and/or neural processing measures can forecast the transition from occasional to problematic stimulant use. METHODS: Occasional stimulant users completed a Risky Gains Task during functional magnetic resonance imaging and were followed up 3 years later. Categorical analyses tested whether blood oxygen level-dependent (BOLD) responses differentiated occasional stimulant users who became problem stimulant users (n = 35) from those who desisted from stimulant use (n = 75) at follow-up. Dimensional analyses (regardless of problem stimulant user or desisted stimulant use status; n = 144) tested whether BOLD responses predicted baseline and follow-up stimulant and marijuana use. RESULTS: Categorical results indicated that relative to those who desisted from stimulant use, problem stimulant users 1) made riskier decisions after winning feedback; 2) exhibited lower frontal, insular, and striatal BOLD responses to win/loss feedback after making risky decisions; and 3) displayed lower thalamic but greater temporo-occipital BOLD responses to risky losses than to risky wins. In comparison, dimensional results indicated that lower BOLD signals to risky choices than to safe choices in frontal, striatal, and additional regions predicted greater marijuana use at follow-up. CONCLUSIONS: Taken together, blunted frontostriatal signals during risky choices may quantify vulnerability to future marijuana consumption, whereas blunted frontostriatal signals to risky outcomes mark risk for future stimulant use disorder. These behavioral and neural processing measures may prove to be useful for identifying ultra-high risk individuals prior to onset of problem drug use.

Chronotype differences in cortical thickness: grey matter reflects when you go to bed.

Based on individual circadian cycles and associated cognitive rhythms, humans can be classified via standardised self-reports as being early (EC), late (LC) and intermediate (IC) chronotypes. Alterations in neural cortical structure underlying these chronotype differences have rarely been investigated and are the scope of this study. 16 healthy male ECs, 16 ICs and 16 LCs were measured with a 3 T MAGNETOM TIM TRIO (Siemens, Erlangen) scanner using a magnetization prepared rapid gradient echo sequence. Data were analysed by applying voxel-based morphometry (VBM) and vertex-wise cortical thickness (CTh) analysis. VBM analysis revealed that ECs showed significantly lower grey matter volumes bilateral in the lateral occipital cortex and the precuneus as compared to LCs, and in the right lingual gyrus, occipital fusiform gyrus and the occipital pole as compared to ICs. CTh findings showed lower grey matter volumes for ECs in the left anterior insula, precuneus, inferior parietal cortex, and right pars triangularis than for LCs, and in the right superior parietal gyrus than for ICs. These findings reveal that chronotype differences are associated with specific neural substrates of cortical thickness, surface areas, and folding. We conclude that this might be the basis for chronotype differences in behaviour and brain function. Furthermore, our results speak for the necessity of considering "chronotype" as a potentially modulating factor in all kinds of structural brain-imaging experiments.

Gender differences in the cognitive control of emotion: An fMRI study.

The interaction of emotion and cognition has become a topic of major interest. However, the influence of gender on the interplay between the two processes, along with its neural correlates have not been fully analysed so far. In this functional magnetic resonance imaging (fMRI) study we induced negative emotion using negative olfactory stimulation while male (n=21) and female (n=19) participants performed an n-back verbal working memory task. Based on findings indicating increased emotional reactivity in women, we expected the female participants to exhibit stronger activation in characteristically emotion-associated areas during the interaction of emotional and cognitive processing in comparison to the male participants. Both groups were found to be significantly impaired in their working memory performance by negative emotion induction. However, fMRI analysis revealed distinct differences in neuronal activation between groups. In men, cognitive performance under negative emotion induction was associated with extended activation patterns in mainly prefrontal and superior parietal regions. In women, the interaction between emotion and working memory yielded a significantly stronger response in the amygdala and the orbitofrontal cortex (OFC) compared to their male counterparts. Our data suggest that in women the interaction of verbal working memory and negative emotion is associated with relative hyperactivation in more emotion-associated areas whereas in men regions commonly regarded as important for cognition and cognitive control are activated. These results provide new insights in gender-specific cerebral mechanisms.

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study.

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.

Stability of emotional dysfunctions? A long-term fMRI study in first-episode schizophrenia.

OBJECTIVE: Patients with schizophrenia are characterized by emotional symptoms such as flattened affect which are accompanied by cerebral dysfunctions. This study aimed at determining changes of mood-related neural correlates under standardized pharmacological therapy in first-episode schizophrenia. METHOD: Using fMRI in a longitudinal approach, 10 first-episode schizophrenia patients (6 males) and 10 healthy subjects (same education, gender and age) were investigated during sad and happy mood induction using facial expressions. Reassessments were carried out following 6 months of standardized antipsychotic treatment. Data analysis focussed on therapy-related changes in cerebral activation and on stable, therapy-independent group differences. RESULTS: According to self ratings, mood induction was successful in both groups and did not reveal time-dependent changes. Patients revealed stable hypoactivations in core brain regions of emotional processing like the anterior cingulate cortex, orbitofrontal and temporal areas as well as the hippocampus. Therapy-related signal increases in pre- and postcentral, inferior temporal and frontal areas were restricted to sadness. DISCUSSION: Stable dysfunctions which are unaffected by therapy and symptom improvement were found in cortico-limbic regions crucially involved in emotion processing. They presumably reflect patients' difficulties in emotion regulation and emotional memory processes. However, therapy-related activation changes were also observed and demonstrate efficacy of antipsychotic therapy on improving emotion functionality. They may represent an increased usage of autobiographic emotional memories and an improved strategy to experience an emotion by mirroring someone else's emotions.