Variations in Theta/Beta Ratio and Cognitive Performance in Subpopulations of Subjects with ADHD Symptoms: Towards Neuropsychological Profiling for Patient Subgrouping.

ADHD is a neurodevelopmental disorder appearing in childhood but remaining in many cases in adults. There are both pharmacological and non-pharmacological approaches to treating ADHD, but they do not have the same efficacy in all subjects. Better knowledge of the neurophysiological basis of this disorder will allow for the design of more effective treatments. Studies performing qEEG analysis in children suggest the existence of subgroups of ADHD patients with different neurophysiological traits. There are fewer studies in adults, who might have undergone plastic changes allowing them to cope with ADHD symptoms along with brain maturation. Herein, we study cognitive performance and the theta/beta ratio in young adults with ADHD symptoms. We found that subjects with ADHD symptoms and low working memory performance (n = 30) present higher theta/beta ratios than controls (n = 40) at O2 and T6 in the eyes-closed condition, as well as a tendency toward a higher theta/beta ratio at O1 and Cz. Subjects with ADHD and high working memory performance (n = 50) do not differ from the controls in their theta/beta ratios at any derivation. Our results suggest that neuropsychological profiling could be useful for patient subgrouping. Further research will allow for the distinction of neuropsychological profiles and their neurophysiological correlates, leading to a better classification of ADHD subtypes, thus improving treatment selection.

Personalization of Pharmacological Treatments for ADHD: Why it is Advisable and Possible Options to Achieve it.

Attention-deficit hyperactivity disorder is a neurodevelopmental disorder diagnosed primarily in children, although it is also present in adults. Patients present inattention, impulsivity, and hyperactivity symptoms that create difficulties in their daily lives. Pharmacological treatment with stimulants or non-stimulants is used most commonly to reduce ADHD symptoms. Although generally effective and safe, pharmacological treatments have different effects among patients, including lack of response and adverse reactions. The reasons for these differences are not fully understood, but they may derive from the highly diverse etiology of ADHD. Strategies to guide optimal pharmacological treatment selection based on individual patients' physiological markers are being developed. In this review, we describe the main pharmacological ADHD treatments used and their main drawbacks. We present alternatives under study that would allow the customization of pharmacological treatments to overcome these drawbacks and achieve more reliable improvement of ADHD symptoms.

ADHD: Reviewing the Causes and Evaluating Solutions.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which patients present inattention, hyperactivity, and impulsivity. The etiology of this condition is diverse, including environmental factors and the presence of variants of some genes. However, a great diversity exists among patients regarding the presence of these ADHD-associated factors. Moreover, there are variations in the reported neurophysiological correlates of ADHD. ADHD is often treated pharmacologically, producing an improvement in symptomatology, albeit there are patients who are refractory to the main pharmacological treatments or present side effects to these drugs, highlighting the importance of developing other therapeutic options. Different non-pharmacological treatments are in this review addressed, finding diverse results regarding efficacy. Altogether, ADHD is associated with different etiologies, all of them producing changes in brain development, leading to the characteristic symptomatology of this condition. Given the heterogeneous etiology of ADHD, discussion is presented about the convenience of personalizing ADHD treatment, whether pharmacological or non-pharmacological, to reach an optimum effect in the majority of patients. Approaches to personalizing both pharmacological therapy and neurofeedback are presented.

Sexual Behavior and Synaptic Plasticity.

Although sex drive is present in many animal species, sexual behavior is not static and, like many other behaviors, can be modified by experience. This modification relies on synaptic plasticity, a sophisticated mechanism through which neurons change how they process a given stimulus, and the neurophysiological basis of learning. This review addresses the main plastic effects of steroid sex hormones in the central nervous system (CNS) and the effects of sexual experience on the CNS, including effects on neurogenesis, intracellular signaling, gene expression, and changes in dendritic spines, as well as behavioral changes.

El consumo de riesgo de alcohol y el riesgo de dependencia al alcohol presentan correlatos neurofisiológicos diferentes / Hazardous alcohol consumption and risk of alcohol dependence present different neurophysiological correlates

Introducción. El consumo de riesgo de alcohol (CRA) es un patrón de consumo que puede resultar dañino para el usuario o para los demás. Investigaciones previas sugieren que el CRA y la dependencia al alcohol comparten algunas características neurofisiológicas, pero difieren en otras. Objetivo. Determinar si el CRA y la dependencia al alcohol presentan correlatos neurofisiológicos diferentes. Sujetos y métodos. Doscientos sujetos realizaron la prueba de detección de CRA y riesgo de dependencia al alcohol (DEP). Se realizó un estudio de electroencefalografía cuantitativa para determinar la potencia absoluta, la potencia relativa y la frecuencia media de las bandas delta, theta, alfa y beta en sujetos con CRA, con DEP y controles. Resultados. Un total de 114 sujetos cumplió los criterios de inclusión. El grupo con CRA presentó mayor potencia absoluta, mayor potencia relativa y menor frecuencia media de la banda beta en comparación con los controles, mientras que el grupo con DEP presentó menor potencia absoluta de la banda delta que los controles. Conclusiones. El DEP y el CRA presentan diferentes correlatos neurofisiológicos. Hay un efecto importante de la gravedad de la dependencia al alcohol sobre sus correlatos neurofisiológicos. Nuestros resultados apoyan la existencia de dos tipos distintos de desinhibición conductual

Introduction. Hazardous alcohol consumption (HAC) is a pattern of alcohol use that may result in harm for the user and/or for those around them. Prior research has suggested that HAC and alcohol dependence share some neurophysiological features but differ in others. Aim. To determine whether HAC and alcohol dependence presented different neurophysiological correlates. Subjects and methods. Two hundred subjects were screened for HAC or alcohol dependence. A quantitative electroencephalographic analysis of delta, theta, alpha and beta absolute power, relative power and mean frequency in subjects with HAC but not alcohol dependence, subjects with risk of alcohol dependence and controls was performed. Results. One hundred and fourteen subjects met inclusion criteria. The HAC group presented with higher beta absolute power and relative power, as well as a lower beta mean frequency than the control group, while the group with risk of alcohol dependence presented lower delta absolute power than controls. Conclusions. HAC and risk of alcohol dependence present different neurophysiological correlates. There is an important effect of the severity of alcohol dependence on neurophysiological correlates of this condition. Our results support the existence of two different types of behavioral disinhibition

The role of dopamine D2 receptors in the nucleus accumbens during taste-aversive learning and memory extinction after long-term sugar consumption.

The nucleus accumbens (NAcc) is a forebrain region that may significantly contribute to the integration of taste and visceral signals during food consumption. Changes in dopamine release in the NAcc have been observed during consumption of a sweet taste and during compulsive consumption of dietary sugars, suggesting that NAcc dopaminergic transmission is strongly correlated with taste familiarity and the hedonic value content. NAcc core and shell nuclei are differentially involved during and after sugar exposure and, particularly, previous evidence suggests that dopamine D2 receptors could be related with the strength of the latent inhibition (LI) of conditioned taste aversion (CTA), which depends on the length of the taste stimulus pre-exposure. Thus, the objective of this work was to evaluate, after long-term exposure to sugar, the function of dopaminergic D2 receptors in the NAcc core during taste memory retrieval preference test, and during CTA. Adult rats were exposed during 14days to 10% sugar solution as a single liquid ad libitum. NAcc core bilateral injections of D2 dopamine receptor antagonist, haloperidol (1µg/µL), were made before third preference test and CTA acquisition. We found that sugar was similarly preferred after 3 acute presentations or 14days of continued sugar consumption and that haloperidol did not disrupt this appetitive memory retrieval. Nevertheless, D2 receptors antagonism differentially affects aversive memory formation after acute or long-term sugar consumption. These results demonstrate that NAcc dopamine D2 receptors have a differential function during CTA depending on the degree of sugar familiarity.

Dopaminergic Modulation of Sleep-Wake States.

The role of dopamine in sleep-wake regulation is considered as a wakefulness-promoting agent. For the clinical treatment of excessive daytime sleepiness, drugs have been commonly used to increase dopamine release. However, sleep disorders or lack of sleep are related to several dopaminerelated disorders. The effects of dopaminergic agents, nevertheless, are mediated by two families of dopamine receptors, D1 and D2-like receptors; the first family increases adenylyl cyclase activity and the second inhibits adenylyl cyclase. For this reason, the dopaminergic agonist effects on sleep-wake cycle are complex. Here, we review the state-of-the-art and discuss the different effects of dopaminergic agonists in sleep-wake states, and propose that these receptors account for the affinity, although not the specificity, of several effects on the sleep-wake cycle.

Quantitative electroencephalography analysis in university students with hazardous alcohol consumption, but not alcohol dependence.

Hazardous alcohol consumption is a pattern of consumption that leads to a higher risk of harmful consequences either for the user or for others. This pattern of alcohol consumption has been linked to risky behaviors, accidents, and injuries. Individuals with hazardous alcohol consumption do not necessarily present alcohol dependence; thus, a study of particular neurophysiological correlates of this alcohol consumption pattern needs to be carried out in nondependent individuals. Here, we carried out a quantitative electroencephalography analysis in health sciences university students with hazardous alcohol consumption, but not alcohol dependence (HAC), and control participants without hazardous alcohol consumption or alcohol dependence (NHAC). We analyzed Absolute Power (AP), Relative Power (RP), and Mean Frequency (MF) for beta and theta frequency bands under both eyes closed and eyes open conditions. We found that participants in the HAC group presented higher beta AP at centroparietal region, as well as lower beta MF at frontal and centroparietal regions in the eyes closed condition. Interestingly, participants did not present any change in theta activity (AP, RP, or MF), whereas previous reports indicate an increase in theta AP in alcohol-dependent individuals. Our results partially resemble those found in alcohol-dependent individuals, although are not completely identical, suggesting a possible difference in the underlying neuronal mechanism behind alcohol dependence and hazardous alcohol consumption. Similarities could be explained considering that both hazardous alcohol consumption and alcohol dependence are manifestations of behavioral disinhibition.

Effects of glutamate and its metabotropic receptors class 1 antagonist in appetitive taste memory formation.

Cortical glutamatergic activity is known to be important for memory formation in different learning tasks. For example, glutamate activity in the insular cortex plays an important role in aversive taste memory formation by signaling the unconditioned stimulus. However, the role of glutamate in the insular cortex in appetitive taste learning has remained poorly studied. Therefore, we considered the function of glutamate in attenuation of neophobia, a model of appetitive taste recognition memory. For this purpose, we performed infusions of vehicle, glutamate, a specific mGluR1 antagonist (AIDA) or a combination of glutamate and AIDA at 0 or 30 min, and glutamate or vehicle at 60 min after novel saccharin consumption. Glutamate infusion impaired appetitive taste recognition memory when infused at 0 or 30 min, whereas, AIDA infusions produced enhanced appetitive memory at the same infusion times. Furthermore, when glutamate and AIDA were infused together no effect on attenuation of neophobia was observed. As opposed to shorter infusion times, the administration of glutamate 60 min after the presentation of the saccharin consumption was ineffective in the impairment of the appetitive taste memory. These results are discussed in view of the effect of glutamate and its mGluR1 during the appetitive taste recognition memory formation in the insular cortex.

Sodium butyrate into the insular cortex during conditioned taste-aversion acquisition delays aversive taste memory extinction.

Histone acetylation is one mechanism that promotes gene expression, and it increases during learning of various tasks. Specifically, novel taste consumption produces an increased acetylation of histone lysine residues in the insular cortex (IC), where protein synthesis is crucial during memory consolidation of conditioned taste aversion (CTA). However, the role of this elevated histone acetylation during CTA learning has not been examined directly. Thus, the present study investigated the effects of sodium butyrate (NaBu), a histone deacetylase inhibitor, injected into the IC during CTA acquisition. Male Wistar rats, IC bilaterally implanted, were injected 60 min before saccharine presentation, with a total volume of 0.5 µl of NaBu solution (100, 500, and 10 µg/0.5 µl) or saline; 30 min later animals were injected intraperitoneally with lithium chloride, a malaise-inducing drug. The next day, CTA retrieval was tested. No effects of NaBu were observed during acquisition or retrieval, but during extinction trials, a significant delay in aversive memory extinction was observed in the group injected with the lowest NaBu dose. This result indicates that NaBu in the IC strengthens CTA and delays aversive memory extinction, and suggests that histone acetylation could increase long-term taste-aversive memory strength.

Activation of nucleus accumbens NMDA receptors differentially affects appetitive or aversive taste learning and memory.

Taste memory depends on motivational and post-ingestional consequences; thus, it can be aversive (e.g., conditioned taste aversion, CTA) if a novel, palatable taste is paired with visceral malaise, or it can be appetitive if no intoxication appears after novel taste consumption, and a taste preference is developed.The nucleus accumbens (NAc) plays a role in hedonic reactivity to taste stimuli, and recent findings suggest that reward and aversion are differentially encoded by the activity of NAc neurons. The present study examined whether the requirement for N-methyl-D-aspartate (NMDA) receptors in the NAc core during rewarding appetitive taste learning differs from that during aversive taste conditioning, as well as during retrieval of appetitive vs. aversive taste memory, using the taste preference or CTA model, respectively. Bilateral infusions of NMDA (1 µg/µl, 0.5 µl) into the NAc core were performed before acquisition or before retrieval of taste preference or CTA. Activation of NMDA receptors before taste preference training or CTA acquisition did not alter memory formation. Furthermore, NMDA injections before aversive taste retrieval had no effect on taste memory; however, 24 h later, CTA extinction was significantly delayed. Also, NMDA injections, made before familiar appetitive memory retrieval, interrupted the development of taste preference and produced a preference delay 24 h later. These results suggest that memory formation for a novel taste produces neurochemical changes in the NAc core that have differential requirements for NMDA receptors during retrieval of appetitive or aversive memory.

ß-Adrenergic receptors in the insular cortex are differentially involved in aversive vs. incidental context memory formation.

The goal of this research was to determine the effects of ß-adrenergic antagonism in the IC before or after inhibitory avoidance (IA) training or context pre-exposure in a latent inhibition protocol. Pretraining intra-IC infusion of the ß-adrenergic antagonist propranolol disrupted subsequent IA retention and impaired latent inhibition of IA, but had no effect on formation of memory for an inert context (termed incidental memory). These results indicate that IC ß-adrenergic receptors are necessary for memory acquisition of an aversive, but not an inconsequential, context. Nevertheless, subsequent association of a familiar and hitherto inconsequential context with an unconditioned stimulus (US) does require activation of these receptors during its initial acquisition.

Blockade of nucleus basalis magnocellularis or activation of insular cortex histamine receptors disrupts formation but not retrieval of aversive taste memory.

Recent research, using several experimental models, demonstrated that the histaminergic system is clearly involved in memory formation. This evidence suggested that during different associative learning tasks, histamine receptor subtypes have opposite functions, related to the regulation of cortical cholinergic activity. Given that cortical cholinergic activity and nucleus basalis magnocellularis (NBM) integrity are needed during taste memory formation, the aim of this study was to determine the role of histamine receptors during conditioned taste aversion (CTA). We evaluated the effects of bilateral infusions of 0.5 microl of pyrilamine (100 mM), an H(1) receptor antagonist, into the NBM, or of R-alpha-methylhistamine (RAMH) (10 mM), an H(3) receptor agonist, into the insular cortex of male Sprague-Dawley rats 20 min before acquisition and/or retrieval of conditioned taste aversion. The results showed that blockade of H(1) receptors in NBM or activation of H(3) receptors in the insular cortex impairs formation but not retrieval of aversive taste memory. These results demonstrated differential roles for histamine receptors in two important areas for taste memory formation and suggest that these effects could be related with the cortical cholinergic activity modulation during CTA acquisition.

Taste memory formation: latest advances and challenges.

Taste memory has been a useful model for studying memory formation; using different approaches ranging from lesion studies, analysis of receptor and neurotransmitter activity, and measurement of intracellular signaling mechanisms or gene expression, it has been possible to describe processes which may be involved in several types of memory. Taste memory includes the recognition of a taste as well as its characteristics related to the hedonic value, degree of familiarity, and the nutritive or toxic properties associated with that taste. In terms of evolutionary adaptation, taste memory is necessary for the proper identification of available nutritive foods and, of course, is essential to avoid deadly toxins. This review summarizes the current knowledge of taste memory, describing the evidence obtained using non-associative and associative taste learning models by manipulating the different structures involved in the formation and expression of taste memory. Pharmacological, biochemical, and molecular data are shown for each structure and subsequently current theories are presented about possible inter-structural interactions taking part in taste memory formation. Finally, we describe how the study of taste memory can reveal basic mechanisms of learning, raising issues that might apply to learning processes in general.

Taste novelty induces intracellular redistribution of NR2A and NR2B subunits of NMDA receptor in the insular cortex.

Taste recognition memory is a process by which animals associate a taste previously experienced with its gastric consequences. Novel taste presentation induces in the insular cortex biochemical modifications that decrease after the taste becomes familiar. Here we show that, in this cortex, consumption of a novel taste produces an increase of the NR2A and NR2B subunits of the NMDA receptor in the detergent resistant membrane (DRM) fraction. This increase did not occur in the adjacent parietal cortex, was not due to a change in the total amount of protein, and is related with the novelty of the stimulus since it was reduced after the taste became familiar. Furthermore, NR2A and NR2B subunits increase in the DRM was blocked by the injection of a muscarinic acetylcholine receptor antagonist. These results suggest that modulation of NMDA receptors in the insular cortex through the increase of its NR2A and NR2B subunits in the DRM is involved in the taste memory formation via a cholinergic process.

PKC blockade differentially affects aversive but not appetitive gustatory memories.

After consumption of a new taste, there are mainly two possible outcomes for the establishment of a taste memory, either it will be aversive or safe depending on the consequences of taste consumption. It has been proposed that both types of learning share a common initial taste memory trace, which will lead to two different memory traces, safe or aversive. To study the role of PKC activity in aversive or safe taste memory formation, we administered chelerythrine, a PKC inhibitor, into the insular cortex or parietal cortex 20 min before conditioned taste aversion or attenuation of neophobia training. The results suggest that PKC activity is needed in the insular cortex for the establishment of aversive taste memory, but not for safe taste memory.

Taste memory formation: role of nucleus accumbens.

When a novel taste has been associated with postingestive malaise, animals recognize this taste as aversive. This associative learning is known as conditioned taste aversion. However, when an animal consumes a novel taste and no aversive consequences follow, it becomes recognized as a safe signal, leading to an increase in its consumption in subsequent presentations. In this review, we will discuss the results related to the taste memory formation focusing particularly on the nucleus accumbens (NAcc). The NAcc keeps projections with amygdala, insular cortex, parabrachial nucleus, and nucleus of the solitary tract areas important for taste memory formation. We will review the evidence relating to how the NAcc could be involved in taste memory formation, due to its role in the taste memory trace formation and its role in the association of the conditioned stimulus-unconditioned stimulus, and finally the retrieval of taste memory. In this context, we will review the participation of the cholinergic, dopaminergic, and glutamatergic systems in the NAcc during taste memory formation.

Cholinergic dependence of taste memory formation: evidence of two distinct processes.

Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animal's survival. A lack of recognition of a taste's consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.