Methylphenidate as a treatment option for substance use disorder: a transdiagnostic perspective.

A transition in viewing mental disorders from conditions defined as a set of unique characteristics to one of the quantitative variations on a collection of dimensions allows overlap between disorders. The overlap can be utilized to extend to treatment approaches. Here, we consider the overlap between attention-deficit/hyperactivity disorder and substance use disorder to probe the suitability to use methylphenidate as a treatment for substance use disorder. Both disorders are characterized by maladaptive goal-directed behavior, impaired cognitive control, hyperactive phasic dopaminergic neurotransmission in the striatum, prefrontal hypoactivation, and reduced frontal cortex gray matter volume/density. In addition, methylphenidate has been shown to improve cognitive control and normalize associated brain activation in substance use disorder patients and clinical trials have found methylphenidate to improve clinical outcomes. Despite the theoretical basis and promising, but preliminary, outcomes, many questions remain unanswered. Most prominent is whether all patients who are addicted to different substances may equally profit from methylphenidate treatment.

Task-specific subnetworks extend from prefrontal cortex to striatum.

Functional magnetic resonance imaging (fMRI) studies on the dynamic representation of task content focus preferentially on the cerebral cortex. However, neurophysiological studies report coding of task-relevant features also by neurons in the striatum, suggesting basal ganglia involvement in cognitive decision-making. Here we use fMRI data to show that also in humans the striatum is an integrated part of the cognitive brain network. Twelve participants performed 3 cognitive tasks in the scanner, i.e., the Eriksen flanker task, a 2-back matching spatial working memory task, and a response scheme switching task. First, we use region of interest-based multivariate pattern classification to demonstrate that each task reliably induces a unique activity pattern in the striatum and in the lateral prefrontal cortex. We show that the three tasks can also be distinguished in putamen, caudate nucleus and ventral striatum alone. We additionally establish that the contribution of striatum to cognition is not sensitive to habituation or learning. Secondly, we use voxel-to-voxel functional connectivity to establish that voxels in the lateral prefrontal cortex and in the striatum that prefer the same task show significantly stronger functional coupling than voxel pairs in these remote structures that prefer different tasks. These results suggest that striatal neurons form subnetworks with cognition-related regions of the prefrontal cortex. These remote neuron populations are interconnected via functional couplings that exceed the time of execution of the specific tasks.

Object Recognition and Dorsal Stream Vulnerabilities in Children With Early Brain Damage.

Aim: Visual functions of the dorsal stream are considered vulnerable in children with early brain damage. Considering the recognition of objects in suboptimal representations a dorsal stream dysfunction, we examined whether children with early brain damage and impaired object recognition had either general or selective dorsal stream dysfunctions. Method: In a group of children with early brain damage (n = 48) we evaluated the dorsal stream functioning. To determine whether these patients had an increased risk of a dorsal stream dysfunction we compared the percentage of patients with impaired object recognition, assessed with the L94, with the estimated base rate. Then we evaluated the performance levels on motion perception, visual attention and visuomotor tasks in patients with (n = 18) and without (n = 11) object recognition abnormalities. A general dorsal stream dysfunction was considered present if a patient showed at least one abnormally low score in two out of three additional dorsal stream functions. Results: Six of the eighteen (33.3%) patients with object recognition problems scored abnormally low on at least two additional dorsal stream functions. This was significantly higher than the base rate (p = 0.01). The difference of 24.1% between the patients with and without object recognition problems was not significant. Of the patients with object recognition problems 72.2% had at least 1 dorsal weakness, whereas this was only the case in 27.3% of patients without object recognition problems. Compared to patients with normal object recognition, patients with object recognition problems scored significantly more abnormally low on motion perception and visual attention (ps = 0.03) but did not differ on visuomotor skills. Conclusion: Children with object recognition problems seem at risk for other dorsal stream dysfunctions, but dysfunctions might be rather specific than general. Multiple functions/aspects should be evaluated in neuropsychological assessment of children at risk.

Clinical Assessment of Visual Motion Perception in Children With Brain Damage: A Comparison With Base Rates and Control Sample.

Aim: In this study, we examined (1) the presence of abnormally low scores (below 10th percentile) in various visual motion perception aspects in children with brain damage, while controlling for their cognitive developmental delay; (2) whether the risk is increased in comparison with the observation and expectation in a healthy control group and healthy population. Methods: Performance levels of 46 children with indications of brain damage (Mage = 7y4m, SD = 2y4m) on three visual motion perception aspects (global motion, motion speed, motion-defined form) were evaluated. We used developmental age as entry of a preliminary reference table to classify the patient's performance levels. Then we compared the percentages of abnormally low scores with percentages expected in the healthy population using estimated base rates and the observed percentages in the control sample (n = 119). Results: When using developmental age as reference level, the percentage of low scores on at least one of the three tasks was significantly higher than expected in the healthy population [19/46, 41% (95%CI: 28-56%), p = 0.03]. In 15/19 (79% [95%CI: 61-97%] patients only one aspect of motion perception was affected. Four patients performed abnormally low on two out of three tasks, which is also higher than expected (4/46, 8.7%, 95%CI: 2.4-20.8% vs. 2.1%; z = 2.61, p < 0.01). The observed percentages in the patient group were also higher than found in the control group. Interpretation: There is some evidence that children with early brain damage have an increased risk of isolated and combined motion perception problems, independent of their performance IQ.

Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users.

Cannabis is the most commonly used illicit drug in the world. However, because of a changing legal landscape and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly cannabis impairment. Importantly, a growing body of evidence suggests that regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo-controlled, cross-over study assessed the acute influence of cannabis on the brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional and 12 chronic cannabis users received acute doses of cannabis (300-µg/kg delta-9-tetrahydrocannabinol) and placebo and underwent ultrahigh field functional magnetic resonance imaging and magnetic resonance spectroscopy. In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, namely, decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in chronic users. The finding that cannabis altered circuitry and distorted behavior in occasional, but not chronic users, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users. Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment, of which is important to understand in the context of the long-term therapeutic use of cannabis-based medications, as well as in the context of public health and safety of cannabis use when performing day-to-day operations.

Antenatal maternal anxiety modulates the BOLD response in 20-year-old men during endogenous cognitive control.

Evidence is building for an association between the level of anxiety experienced by a mother during pregnancy and offspring cognition and structural and functional brain correlates. The current study uses fMRI to examine the association between prenatal exposure to maternal anxiety and brain activity associated with endogenous versus exogenous cognitive control in 20-year-old males. Endogenous cognitive control refers to the ability to generate control over decisions, strategies, conflicting information and so on, from within oneself without external signals, while exogenous control is triggered by external signals. In line with previous results of this long-term follow-up study we found that 20-year-olds of mothers reporting high levels of anxiety during weeks 12-22 of pregnancy exhibited a different pattern of decision making in a Gambling paradigm requiring endogenous cognitive control, compared to adults of mothers reporting low to average levels of anxiety. Moreover, the blood oxygenation level dependent (BOLD) response in a number of prefrontal cortical areas was modulated by the level of antenatal maternal anxiety. In particular, a number of right lateralized clusters including inferior frontal junction, that were modulated in the adults of mothers reporting low to average levels of anxiety during pregnancy by a task manipulation of cognitive control, were not modulated by this manipulation in the adults of mothers reporting high levels of anxiety during pregnancy. These differences in brain functional correlates provide a neurobiological underpinning for the hypothesis of an association between exposure to maternal anxiety in the prenatal life period and a deficit in endogenous cognitive control in early adulthood.

Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity.

Cannabis is the most commonly used illicit drug and is known to alter state of consciousness and impair neurocognitive function. However, the mechanisms underlying these effects have yet to be fully elucidated. Rodent studies suggest that Δ9-tetrahydrocannabinol (THC) activates dopaminergic neurons in the limbic system, subsequently enhancing dopamine, which is implicated in the rewarding effects of cannabis. Additional evidence suggests that THC may act indirectly on dopamine firing by modulating GABA and glutamate release. This double-blind, placebo-controlled study assessed the acute influence of two doses of THC on brain kinetics of glutamate, GABA, and dopamine, in relation to behavioral outcomes, by using magnetic resonance spectroscopy and functional magnetic resonance imaging. Twenty occasional cannabis users received acute doses of cannabis (300 µg/kg THC) and placebo, in one of two dose regimes (full dose and divided dose), during two separate testing days. Administration of THC increased striatal glutamate concentrations, and dopamine as indicated by a reduction in functional connectivity (FC) between the nucleus accumbens (NAc) and cortical areas. Alterations in glutamate and FC were dose dependent and evident in the full dose group where THC serum concentrations exceeded 2 ng/ml at T-max. Average glutamate changes correlated strongly with FC alterations. Additionally, THC induced changes in FC correlated with feelings of subjective high and decreased performance on an attention task. Taken together, this suggests that THC elicits subjective and cognitive alterations via increased striatal dopaminergic activity and loss of corticostriatal connectivity, which is associated with an increase in striatal glutamate.

Age-related differences in task-induced brain activation is not task specific: Multivariate pattern generalization between metacognition, cognition and perception.

Adolescence is associated with widespread maturation of brain structures and functional connectivity profiles that shift from local to more distributed and better integrated networks, which are active during a variety of cognitive tasks. Nevertheless, the approach to examine task-induced developmental brain changes is function-specific, leaving the question open whether functional maturation is specific to the particular cognitive demands of the task used, or generalizes across different tasks. In the present study we examine the hypothesis that functional brain maturation is driven by global changes in how the brain handles cognitive demands. Multivariate pattern classification analysis (MVPA) was used to examine whether age discriminative task-induced activation patterns generalize across a wide range of information processing levels. 25 young (13-years old) and 22 old (17-years old) adolescents performed three conceptually different tasks of metacognition, cognition and visual processing. MVPA applied within each task indicated that task-induced brain activation is consistent and reliably different between ages 13 and 17. These age-discriminative activation patterns proved to be common across the different tasks used, despite the differences in cognitive demands and brain structures engaged by each of the three tasks. MVP classifiers trained to detect age-discriminative patterns in brain activation during one task were significantly able to decode age from brain activation maps during execution of other tasks with accuracies between 63 and 75%. The results emphasize that age-specific characteristics of task-induced brain activation have to be understood at the level of brain-wide networks that show maturational changes in their organization and processing efficacy during adolescence.

Orbital and Medial Prefrontal Cortex Functional Connectivity of Major Depression Vulnerability and Disease.

BACKGROUND: Pathophysiology models of major depression (MD) center on the dysfunction of various cortical areas within the orbital and medial prefrontal cortex. While independent structural and functional abnormalities in these areas are consistent findings in MD, the complex interactions among them and the rest of the cortex remain largely unexplored. METHODS: We used resting-state functional magnetic resonance imaging connectivity to systematically map alterations in the communication between orbital and medial prefrontal cortex fields and the rest of the brain in MD. Functional connectivity (FC) maps from participants with current MD (n = 35), unaffected first-degree relatives (n = 36), and healthy control subjects (n = 38) were subjected to conjunction analyses to distinguish FC markers of MD vulnerability and FC markers of MD disease. RESULTS: FC abnormalities in MD vulnerability were found for dorsal medial wall regions and the anterior insula and concerned altered communication of these areas with the inferior parietal cortex and dorsal posterior cingulate, occipital areas and the brainstem. FC aberrations in current MD included the anterior insula, rostral and dorsal anterior cingulate cortex, and lateral orbitofrontal areas and concerned altered communication with the dorsal striatum, the cerebellum, the precuneus, the anterior prefrontal cortex, somatomotor cortex, dorsolateral prefrontal cortex, and visual areas in the occipital and inferior temporal lobes. CONCLUSIONS: Functionally delineated parcellation maps can be used to identify putative connectivity markers in extended cortical regions such as the orbital and medial prefrontal cortex. The anterior insula and the rostral anterior cingulate cortex play a central role in the pathophysiology of MD, being consistently implicated both in the MD vulnerability and MD disease states.

Functional connectivity of task context representations in prefrontal nodes of the multiple demand network.

A subset of regions in the lateral and medial prefrontal cortex and the anterior insula increase their activity level whenever a cognitive task becomes more demanding, regardless of the specific nature of this demand. During execution of a task, these areas and the surrounding cortex temporally encode aspects of the task context in spatially distributed patterns of activity. It is not clear whether these patterns reflect underlying anatomical subnetworks that still exist when task execution has finished. We use fMRI in 12 participants performing alternating blocks of three cognitive tasks to address this question. A first data set is used to define multiple demand regions in each participant. A second dataset from the same participants is used to determine multiple demand voxel assemblies with a preference for one task over the others. We then show that these voxels remain functionally coupled during execution of non-preferred tasks and that they exhibit stronger functional connectivity during rest. This indicates that the assemblies of task preference sharing voxels reflect patterns of underlying anatomical connections. Moreover, we show that voxels preferring the same task have more similar whole brain functional connectivity profiles that are consistent across participants. This suggests that voxel assemblies differ in patterns of input-output connections, most likely reflecting task demand-specific information exchange.

Should we add visual acuity ratios to referral criteria for potential cerebral visual impairment? / ¿Se deberían incorporar los ratios de agudeza visual a los criterios de derivación en los casos de discapacidad visual cerebral potencial?

Purpose: To determine whether the assessment of visual acuity ratios might improve the referral of children with (sub)normal visual acuity but at risk of cerebral visual impairment. Methods: In an exploratory study, we assessed visual acuity, crowding ratio and the ratios between grating acuity (Teller Acuity Cards-II) and optotype acuity (Cambridge Crowding Cards) in 60 typically developing school children (mean age 5y8m±1y1m), 21 children with ocular abnormalities only (5y7m±1y9m) and 26 children with (suspected) brain damage (5y7m±1y11m). Sensitivities and specificities were calculated for targets and controls from the perspective of different groups of diagnosticians: youth health care professionals (target: children with any visual abnormalities), ophthalmologists and low vision experts (target: children at risk of cerebral visual impairment). Results: For youth health care professionals subnormal visual acuity had the best sensitivity (76%) and specificity (70%). For ophthalmologists and low vision experts the crowding ratio had the best sensitivity (67%) and specificity (79 and 86%). Conclusion: Youth health care professionals best continue applying subnormal visual acuity for screening, whereas ophthalmologists and low vision experts best add the crowding ratio to their routine diagnostics, to distinguish children at risk of visual impairment in the context of brain damage from children with ocular pathology only (AU)

Objetivo: Determinar si la valoración de los ratios de agudeza visual en niños podría mejorar la derivación de niños con agudeza visual (sub)normal, pero con riesgo de discapacidad visual cerebral. Métodos: En un estudio exploratorio, valoramos la agudeza visual, el ratio de aglomeración y los ratios comprendidos entre la agudeza de difracción (Teller Acuity Cards-II) y la agudeza visual de optotipos (Cambridge Crowding Cards) en 60 escolares con desarrollo normal (edad media 5.8±1,1), 21 con anomalías oculares únicamente (5,7±1,9) y 26 niños con daño cerebral (sospechado) (5,7±1,1). Las sensibilidades y especificidades fueron calculados para los casos de estudio y controles desde la perspectiva de diferentes grupos de evaluadores: profesionales sanitarios para jóvenes (objetivo: niños con cualquier anomalía visual), oftalmólogos y expertos en baja visión (objetivo: niños con riesgo de discapacidad visual cerebral). Resultados: Para los profesionales sanitarios para jóvenes la agudeza visual obtuvo la mejor sensibilidad (76%) y especificidad (70%). Para los oftalmólogos y los expertos en baja visión el ratio de aglomeración obtuvo la mejor sensibilidad (67%) y especificidad (79 y 86%). Conclusión: Los profesionales sanitarios para jóvenes siguen aplicando la agudeza visual inferior a lo normal en los exámenes visuales, mientras que los oftalmólogos y los expertos en baja visión incorporan el ratio de aglomeración a sus diagnósticos rutinarios, para distinguir a los niños con riesgo de discapacidad visual en el contexto del daño cerebral, de los niños con patología ocular únicamente (AU)

Human orbital and anterior medial prefrontal cortex: Intrinsic connectivity parcellation and functional organization.

The orbital and medial prefrontal cortex (OMPFC) has been implicated in decision-making, reward and emotion processing, and psychopathology, such as depression and obsessive-compulsive disorder. Human and monkey anatomical studies indicate the presence of various cortical subdivisions and suggest that these are organized in two extended networks, a medial and an orbital one. Attempts have been made to replicate these neuroanatomical findings in vivo using MRI techniques for imaging connectivity. These revealed several consistencies, but also many inconsistencies between reported results. Here, we use fMRI resting-state functional connectivity (FC) and data-driven modularity optimization to parcellate the OMPFC to investigate replicability of in vivo parcellation more systematically. By collecting two resting-state data sets per participant, we were able to quantify the reliability of the observed modules and their boundaries. Results show that there was significantly more than chance overlap in modules and their boundaries at the level of individual data sets. Moreover, some of these consistent boundaries significantly co-localized across participants. Hierarchical clustering showed that the whole-brain FC profiles of the OMPFC subregions separate them in two networks, a medial and orbital one, which overlap with the organization proposed by Barbas and Pandya (J Comp Neurol 286:353-375, 1989) and Ongür and Price (Cereb Cortex 10:206-219, 2000). We conclude that in vivo resting-state FC can delineate reliable and neuroanatomically plausible subdivisions that agree with established cytoarchitectonic trends and connectivity patterns, while other subdivisions do not show the same consistency across data sets and studies.

Should we add visual acuity ratios to referral criteria for potential cerebral visual impairment?

PURPOSE: To determine whether the assessment of visual acuity ratios might improve the referral of children with (sub)normal visual acuity but at risk of cerebral visual impairment. METHODS: In an exploratory study, we assessed visual acuity, crowding ratio and the ratios between grating acuity (Teller Acuity Cards-II) and optotype acuity (Cambridge Crowding Cards) in 60 typically developing school children (mean age 5y8m±1y1m), 21 children with ocular abnormalities only (5y7m±1y9m) and 26 children with (suspected) brain damage (5y7m±1y11m). Sensitivities and specificities were calculated for targets and controls from the perspective of different groups of diagnosticians: youth health care professionals (target: children with any visual abnormalities), ophthalmologists and low vision experts (target: children at risk of cerebral visual impairment). RESULTS: For youth health care professionals subnormal visual acuity had the best sensitivity (76%) and specificity (70%). For ophthalmologists and low vision experts the crowding ratio had the best sensitivity (67%) and specificity (79 and 86%). CONCLUSION: Youth health care professionals best continue applying subnormal visual acuity for screening, whereas ophthalmologists and low vision experts best add the crowding ratio to their routine diagnostics, to distinguish children at risk of visual impairment in the context of brain damage from children with ocular pathology only.

Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication.

Drugs of abuse stimulate striatal dopamine release and activate reward pathways. This study examined the impact of alcohol and cannabis marketing on the reward circuit in alcohol and cannabis users while sober and intoxicated. It was predicted that alcohol and cannabis marketing would increase striatal activation when sober and that reward sensitivity would be less during alcohol and cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21) participated in a mixed factorial study involving administration of alcohol and placebo in the alcohol group and cannabis and placebo in the cannabis group. Non-drug users (n = 20) served as between group reference. Brain activation after exposure to alcohol and cannabis marketing movies was measured using functional magnetic resonance imaging and compared between groups while sober and compared with placebo while intoxicated. Implicit alcohol and cannabis cognitions were assessed by means of a single-category implicit association test. Alcohol and cannabis marketing significantly increased striatal BOLD activation across all groups while sober. Striatal activation however decreased during intoxication with alcohol and cannabis. Implicit associations with cannabis marketing cues were significantly more positive in alcohol and cannabis users as compared with non-drug using controls. Public advertising of alcohol or cannabis use elicits striatal activation in the brain's reward circuit. Reduction of marketing would reduce brain exposure to reward cues that motivate substance use. Conversely, elevated dopamine levels protect against the reinforcing potential of marketing.

Intrinsic functional architecture of the macaque dorsal and ventral lateral frontal cortex.

Investigations of the cellular and connectional organization of the lateral frontal cortex (LFC) of the macaque monkey provide indispensable knowledge for generating hypotheses about the human LFC. However, despite numerous investigations, there are still debates on the organization of this brain region. In vivo neuroimaging techniques such as resting-state functional magnetic resonance imaging (fMRI) can be used to define the functional circuitry of brain areas, producing results largely consistent with gold-standard invasive tract-tracing techniques and offering the opportunity for cross-species comparisons within the same modality. Our results using resting-state fMRI from macaque monkeys to uncover the intrinsic functional architecture of the LFC corroborate previous findings and inform current debates. Specifically, within the dorsal LFC, we show that 1) the region along the midline and anterior to the superior arcuate sulcus is divided in two areas separated by the posterior supraprincipal dimple, 2) the cytoarchitectonically defined area 6DC/F2 contains two connectional divisions, and 3) a distinct area occupies the cortex around the spur of the arcuate sulcus, updating what was previously proposed to be the border between dorsal and ventral motor/premotor areas. Within the ventral LFC, the derived parcellation clearly suggests the presence of distinct areas: 1) an area with a somatomotor/orofacial connectional signature (putative area 44), 2) an area with an oculomotor connectional signature (putative frontal eye fields), and 3) premotor areas possibly hosting laryngeal and arm representations. Our results illustrate in detail the intrinsic functional architecture of the macaque LFC, thus providing valuable evidence for debates on its organization.NEW & NOTEWORTHY Resting-state functional MRI is used as a complementary method to invasive techniques to inform current debates on the organization of the macaque lateral frontal cortex. Given that the macaque cortex serves as a model for the human cortex, our results help generate more fine-tuned hypothesis for the organization of the human lateral frontal cortex.

Reverse inference of memory retrieval processes underlying metacognitive monitoring of learning using multivariate pattern analysis.

Monitoring of learning is only accurate at some time after learning. It is thought that immediate monitoring is based on working memory, whereas later monitoring requires re-activation of stored items, yielding accurate judgements. Such interpretations are difficult to test because they require reverse inference, which presupposes specificity of brain activity for the hidden cognitive processes. We investigated whether multivariate pattern classification can provide this specificity. We used a word recall task to create single trial examples of immediate and long term retrieval and trained a learning algorithm to discriminate them. Next, participants performed a similar task involving monitoring instead of recall. The recall-trained classifier recognized the retrieval patterns underlying immediate and long term monitoring and classified delayed monitoring examples as long-term retrieval. This result demonstrates the feasibility of decoding cognitive processes, instead of their content.

The association between cortisol and the BOLD response in male adolescents undergoing fMRI.

MRI participation has been shown to induce subjective and neuroendocrine stress reactions. A recent aging study showed that cortisol levels during fMRI have an age-dependent effect on cognitive performance and brain functioning. The present study examined whether this age-specific influence of cortisol on behavioral and brain activation levels also applies to adolescence. Salivary cortisol as well as subjective experienced anxiety were assessed during the practice session, at home, and before, during and after the fMRI session in young versus old male adolescents. Cortisol levels were enhanced pre-imaging relative to during and post-imaging in both age groups, suggesting anticipatory stress and anxiety. Overall, a negative correlation was found between cortisol output during the fMRI experiment and brain activation magnitude during performance of a gambling task. In young but not in old adolescents, higher cortisol output was related to stronger deactivation of clusters in the anterior and posterior cingulate cortex. In old but not in young adolescents, a negative correlation was found between cortisol and activation in the inferior parietal and in the superior frontal cortex. In sum, cortisol increased the deactivation of several brain areas, although the location of the affected areas in the brain was age-dependent. The present findings suggest that cortisol output during fMRI should be considered as confounder and integrated in analyzing developmental changes in brain activation during adolescence.

Comparative analysis of the macroscale structural connectivity in the macaque and human brain.

The macaque brain serves as a model for the human brain, but its suitability is challenged by unique human features, including connectivity reconfigurations, which emerged during primate evolution. We perform a quantitative comparative analysis of the whole brain macroscale structural connectivity of the two species. Our findings suggest that the human and macaque brain as a whole are similarly wired. A region-wise analysis reveals many interspecies similarities of connectivity patterns, but also lack thereof, primarily involving cingulate regions. We unravel a common structural backbone in both species involving a highly overlapping set of regions. This structural backbone, important for mediating information across the brain, seems to constitute a feature of the primate brain persevering evolution. Our findings illustrate novel evolutionary aspects at the macroscale connectivity level and offer a quantitative translational bridge between macaque and human research.

Mapping the hierarchical layout of the structural network of the macaque prefrontal cortex.

A consensus on the prefrontal cortex (PFC) holds that it is pivotal for flexible behavior and the integration of the cognitive, affective, and motivational domains. Certain models have been put forth and a dominant model postulates a hierarchical anterior-posterior gradient. The structural connectivity principles of this model dictate that increasingly anterior PFC regions exhibit more efferent connections toward posterior ones than vice versa. Such hierarchical asymmetry principles are thought to pertain to the macaque PFC. Additionally, the laminar patterns of the connectivity of PFC regions can be used for defining hierarchies. In the current study, we formally tested the asymmetry-based hierarchical principles of the anterior-posterior model by employing an exhaustive dataset on macaque PFC connectivity and tools from network science. On the one hand, the asymmetry-based principles and predictions of the hierarchical anterior-posterior model were not confirmed. The wiring of the macaque PFC does not fully correspond to the principles of the model, and its asymmetry-based hierarchical layout does not follow a strict anterior-posterior gradient. On the other hand, our results suggest that the laminar-based hierarchy seems a more tenable working hypothesis for models advocating an anterior-posterior gradient. Our results can inform models of the human PFC.

The role of P-glycoprotein in CNS antihistamine effects.

RATIONALE: P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates. OBJECTIVES: The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans. METHODS: An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone. RESULTS: The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus. CONCLUSION: It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.