Cortisol responses in children and adults with attention deficit hyperactivity disorder (ADHD): a possible marker of inhibition deficits

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disease whose neurobiological background is not completely understood. It has been proposed that deficits of the inhibitory function with an underactive behavioral inhibition system (BIS) may be in the core of ADHD. In this regard, this review summarizes all studies that examine the involvement of cortisol in ADHD. Differences in cortisol responses from different ADHD subtypes, hyperactive/impulsive, inattentive, and combined, are analyzed. In addition, we examine the role of comorbidities as confounding factors in the study of cortisol in ADHD, including comorbid disruptive behavioral disorder (DBD), as well as anxiety and depressive disorders. Because ADHD is a neurodevelopmental condition and approximately half of the children enter adulthood with the disorder, we review cortisol studies in adults and children separately. Two diverse patterns of cortisol have been reported both in children and adults with ADHD. Blunted cortisol responses to stress are associated with comorbid DBD, whereas high cortisol responses are associated to comorbid anxiety disorders. Nevertheless, the inhibitory deficits in ADHD do not appear to be related directly to cortisol deficits in either children or adults. This review increases our understanding of the heterogeneity of ADHD and could help in determining new strategies for the treatment of these patients. Future studies including gender and a more systematic methodology to study the cortisol response are needed.     

Demographic,developmental and psychosocial predictors of the development of anxiety in adults with ADHD

The purpose of this research was to investigate potential demographic, developmental and psychosocial predictors of anxiety in the context of ADHD. Participants included 267 adults with a diagnosis of ADHD (168 males:99 females) and an age range of 18–70 years (M = 31 years; SD = 10.03 years). A background interview, parent questionnaire and rating scales were used to gather participant information. Correlations, independent t tests and one-way analysis of variances were used to identify variables associated with anxiety, and a stepwise multiple regression was used to identify potential predictors of anxiety. Variables associated with anxiety included childhood aggression, employment status, difficulties making friends, number of children and caffeine intake. Childhood aggression and caffeine intake were the potential predictors. Clinicians should be aware of these potential predictors of anxiety in the context of ADHD in order to minimise the likelihood of the development or maintenance of comorbid anxiety. Future research is needed in order to draw any conclusions on cause and effect.     

The use of compensatory strategies in adults with ADHD symptoms

This study examined the use of compensatory strategies reported by adults with ADHD symptoms and their relation to measures of functioning. Forty-nine adults (55.1 % female) completed a structured diagnostic interview to assess ADHD, and responses were coded for compensatory strategies: Adaptation, Paying Attention, Organization, External Support, and Avoidance. The majority of adults with ADHD symptoms reported using compensatory strategies, and their reported strategy use in childhood was related to their use in adulthood. No gender differences were found in the use of strategies, although Organization and External Support were used more often for inattention than for hyperactive/impulsive symptoms. Use of the compensatory strategy, Adaptation, was significantly related to measures of functioning, and the use of strategies reduced the negative relationship between ADHD symptoms and parenting difficulties. Results encourage the development of compensatory strategies among adults with ADHD symptoms, as well as provide recommendations for treatment programs.     

The quick delay questionnaire: a measure of delay aversion and discounting in adults

Individuals with ADHD often display an altered response to delay. To date, assessment of this has typically involved neuropsychological testing-however, such tests are designed specifically for children and may not be suitable for adults. They are also relatively time-consuming and expensive. In the current paper, we describe the initial validation of a short questionnaire to assess delay-related behaviour in adults. The Quick Delay Questionnaire (QDQ) is a 10-item scale. The questionnaire was administered to 575 participants from the normal population (ranging in age from 18 to 77 years). Forty of the original sample were selected at random and tested 1 week later. Data on ADHD, anxiety and depression were also collected. There were two five-item scales-(1) delay aversion; and (2) delay discounting. These had internal consistency and had good reliability. Subscales were differentially associated with ADHD, anxiety and depression. The QDQ is a potentially valuable way of assessing response to delay in adults. Further work is required to validate the scale against direct observation and neuropsychological assessment in clinically ascertained samples.     

Cognitive behavioural therapy for ADHD in adults: systematic review and meta-analyses

Systematically review and analyse the efficacy of CBT versus treatment as usual in adults with ADHD. The literature was systematically searched ending the 28 March 2014. Standardised mean differences (SMD) and 95 % confidence intervals were calculated. CBT was efficacious in reducing symptoms of ADHD (SDM ?1.0, 95 % CI ?1.5 to ?0.5) when evaluated by the patients, but not when evaluated by a clinician. Symptoms of depression and anxiety were significantly reduced when self-reported (SMD ?1.0, 95 % CI ?1.6 to ?0.5 and ?1.0, 95 % CI ?1.3 to ?0.3, respectively) and evaluated by a clinician (SMD ?0.9, 95 % CI ?1.7 to ?0.2 and ?0.9, 95 % CI ?1.6 to ?0.1). The clinical global impression scores improved more in the group randomised to CBT (?1.0; 95 % CI ?1.6 to ?0.4). CBT seems efficacious in some domains affecting adult patients with ADHD, but needs further evaluation.     

Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review

Attention deficit/hyperactivity disorder (ADHD) involves clinically heterogeneous problems including attention deficits, behavioural hyperactivity and impulsivity. Several animal models of ADHD have been proposed, ranging from models with neurotoxic lesions to genetically manipulated animals. An ADHD model is supposed to show phenomenological similarities with the disorder, i.e. it should mimic the three core symptoms (face validity). A model should also conform to an established or hypothesized pathophysiological basis of the disorder (construct validity). Finally, an animal model should be able to predict previously unknown aspects of the neurobiology of ADHD or to provide potential new treatments (predictive validity). The currently proposed models are heterogeneous with regard to their pathophysiological alterations and their ability to mimic behavioural symptoms and to predict response to medication. This might reflect the heterogeneous nature of ADHD. Since the knowledge about the biology of ADHD from human studies is limited, one cannot at present decide which model best represents ADHD or certain ADHD subtypes. Animal models with good face and predictive validity may be useful for investigations of the underlying biological substrates of ADHD. At present, the models in use should be described as animal models of ADHD-like symptoms rather than models of ADHD.     

Molecular dynamics simulation of TMEM16A channel: Linking structure with gating

TMEM16A, the calcium-activated chloride channel, is broadly expressed and plays pivotal roles in diverse physiological processes. To understand the structural and functional relationships of TMEM16A, it is necessary to fully clarify the structural basis of the gating of the TMEM16A channel. Herein, we performed the protein electrostatic analysis and molecular dynamics simulation on the TMEM16A in the presence and absence of Ca²⁺. Data showed that the separation of TM4 and TM6 causes pore expansion, and Q646 may be a key residue for the formation of π-helix in the middle segment of TM6. Moreover, E705 was found to form a group of H-bond interactions with D554/K588/K645 below the hydrophobic gate to stabilize the closed conformation of the pore in the Ca²⁺-free state. Interestingly, in the Ca²⁺ bound state, the E705 side chain swings 100^o to serve as Ca²⁺-binding coordination and released K645. K645 is closer to the hydrophobic gate in the calcium-bound state, which facilitates the provision of electrostatic forces for chloride ions as the ions pass through the hydrophobic gate. Our findings provide the structural-based insights to understanding the mechanisms of gating of TMEM16A.     

Understanding deficient emotional self-regulation in adults with attention deficit hyperactivity disorder: a controlled study

While symptoms of deficient emotional self-regulation (DESR) such as low frustration tolerance, temper outbursts, emotional impulsivity, and mood lability are commonly associated with attention deficit hyperactivity disorder (ADHD), little is known about their nature. The main aim of this post hoc study was to examine the correlates of DESR in a large sample of adults with and without ADHD. Subjects were 206 adults with ADHD and 123 adults without ADHD from a family study of ADHD. Emotional impulsivity was operationalized using items from the Barkley Current Behavior Scale. Subjects were comprehensively assessed for psychiatric comorbidity using structured diagnostic interview methodology. We used the Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (QLES-Q-SF) and Social Adjustment Scale-Self-report (SAS-SR) to assess quality of life and psychosocial functioning. DESR was more common among ADHD compared with non-ADHD adults, and 55 % of adults with ADHD reported extreme DESR of greater severity than 95 % of control subjects. The association of ADHD and DESR was not entirely accounted for by either current or lifetime comorbid disorders. DESR was also associated with significant functional impairment as evaluated by the QLES-Q-SF and SAS-SR, and with reduced marital status, as well as higher risk for traffic accidents and arrests. DESR adversely impacts quality of life in adults with ADHD. More work is needed to further evaluate DESR in clinical and investigational studies of subjects with ADHD.     

Reduced emotional empathy in adults with subclinical ADHD: evidence from the empathy and systemizing quotient

Studies in children with ADHD suggest impairments in social cognitive functions, whereas studies in adults with ADHD are scarce and inconclusive. The aim of this study was to investigate the relationship between ADHD traits and self-reported social cognitive style in a sample of adults from the general population. For this purpose, a community sample of 685 adults filled out online self-report questionnaires about ADHD symptoms (ADHD Rating Scale, ARS), social cognitive functioning and friendships. The Empathy Quotient (EQ) with the subscales Cognitive Empathy (CE), Emotional Empathy (EE) and Social Skills (SS), and the Systemizing Quotient (SQ) were included for measuring social cognitive style and the Friendship Questionnaire (FQ) for the quality of friendships. Participants who met the DSM-5 criteria on the ARS (‘subclinical ADHD’; n = 56) were compared regarding their social cognitive functioning scores with a control group (n = 56) that was matched for age, sex and student status. With small effect sizes, the subclinical ADHD group showed reduced EE scores on the EQ and a more male social cognitive profile. This result was not influenced by sex or ADHD subtype. This study points to a relationship between traits of ADHD and the emotional aspect of empathy, whereas more complex aspects of empathy were unrelated. These findings should be corroborated in clinical patients with ADHD, employing neuropsychological tests rather than self-report questionnaires.     

Netrin-1 signaling for sensory axons: Involvement in sensory axonal development and regeneration

During development, dorsal root ganglion (DRG) neurons extend their axons toward the dorsolateral part of the spinal cord and enter the spinal cord through the dorsal root entry zone (DREZ). After entering the spinal cord, these axons project into the dorsal mantle layer after a “waiting period” of a few days. We revealed that the diffusible axonal guidance molecule netrin-1 is a chemorepellent for developing DRG axons. When DRG axons orient themselves toward the DREZ, netrin-1 proteins derived from the ventral spinal cord prevent DRG axons from projecting aberrantly toward the ventral spinal cord and help them to project correctly toward the DREZ. In addition to the ventrally derived netrin-1, the dorsal spinal cord cells adjacent to the DREZ transiently express netrin-1 proteins during the waiting period. This dorsally derived netrin-1 contributes to the correct guidance of DRG axons to prevent them from invading the dorsal spinal cord. In general, there is a complete lack of sensory axonal regeneration after a spinal cord injury, because the dorsal column lesion exerts inhibitory activities toward regenerating axons. Netrin-1 is a novel candidate for a major inhibitor of sensory axonal regeneration in the spinal cord; because its expression level stays unchanged in the lesion site following injury, and adult DRG neurons respond to netrin-1-induced axon repulsion. Although further studies are required to show the involvement of netrin-1 in preventing the regeneration of sensory axons in CNS injury, the manipulation of netrin-1-induced repulsion in the CNS lesion site may be a potent approach for the treatment of human spinal injuries.Key words: netrin-1, dorsal root ganglion, axon guidance, chemorepellent, Unc5, spinal cord, axon regenerationDeveloping axons navigate to their targets by responding to attractive and repulsive guidance cues working in a contact-dependent or diffusible fashion in their environment (reviewed in ref. ¹). During early development of the primary sensory system, centrally projecting sensory axons from dorsal root ganglion (DRG) neurons extend toward the dorsolateral region of the spinal cord (Fig. 1A and C), where they enter the spinal cord exclusively through the dorsal root entry zone (DREZ), and never orient themselves toward the notochord or the ventral spinal cord (Fig. 1A; reviewed in ref. ²). We previously showed that the notochord but not the ventral spinal cord secretes semaphorin 3A (Sema3A), which is known to be a chemorepellent for DRG axons at early developmental stages (Fig. 1A).³ This is the reason why DRG axons never project toward the notochord. Along the same line, it is highly possible that the ventral spinal cord may secrete some chemorepulsive cue other than Sema3A for DRG axons.Open in a separate windowFigure 1Netrin-1 plays a critical role in sensory axonal guidance as an axon chemorepellent. (A) A schematic diagram of a thoracic transverse section of an E10 mouse embryo, summarizing the possible mechanism of netrin-1 action in early DRG axonal guidance. When DRG axons project toward the DREZ in the dorsal spinal cord (dSC), ventrally derived netrin-1 chemorepels DRG axons to prevent them from orienting aberrantly toward the ventral spinal cord (vSC) (upper). NC; notochord. In netrin-1-deficient embryos, some DRG axons misorient themselves toward the ventral spinal cord, because of the absence of netrin-1 proteins in the ventral spinal cord (lower). (B) At E12.5 when DRG axons grow to the marginal zone of the spinal cord longitudinally (arrows) to form the dorsal funiculus (DF), netrin-1 proteins are transiently expressed in a subpopulation of dorsal spinal cord cells adjacent to the dorsal funiculus (upper). In netrin-1-deficient embryos, the dorsal funiculus is disorganized because DRG axons are no longer waiting for invading the dorsal mantle layer (lower). (C) Gain-of-function experiments by electroporation confirm the repulsive activity of netrin-1 toward DRG axons. When netrin-1 is misexpressed in the dorsal spinal cord, the number of DRG axons that enter the DREZ is significantly reduced compared with the control, because some DRG axons fail to project toward the DREZ and turn in the wrong direction.After entering the spinal cord, DRG axons grow to the marginal zone of the spinal cord longitudinally to form the dorsal funiculus without projecting to the dorsal mantle layer for a few days (this delay of the axonal projection to the mantle layer is referred to as the ‘waiting period;’ Fig. 1B). A few days later, proprioceptive afferents of DRGs begin to send collaterals into the dorsal layers, and cutaneous afferents project ventrally through the dorsal layers.⁴ This evidence raises the possibility that some repulsive cues transiently prevent the collaterals of DRGs from penetrating the dorsal spinal cord during this waiting period.Netrins are a family of secreted proteins that play a key role in axonal guidance, cell migration, morphogenesis and angiogenesis.⁵ Netrin-1 is a bifunctional axonal guidance cue, attracting some axons including commissural axons via the Deleted in Colorectal Cancer (DCC) receptor and repelling others via Unc5 receptors (reviewed in ref. ⁶). However, it has not been clear whether netrin-1 plays a role in sensory axonal guidance during development.Several observations strongly suggest a role for netrin-1 in DRG axonal guidance as a repulsive guidance cue during development.^7,8 First, in the mouse embryo at embryonic day (E) 10–11.⁵ when many DRG axons orient themselves to reach the DREZ, netrin-1 is strongly expressed in the floor plate of the ventral spinal cord but not in the dorsal spinal cord (Fig. 1A). Second, at E12.5 when DRG neurons extend their axons longitudinally along the dorsolateral margin of the spinal cord, netrin-1 is expressed in the dorsolateral region adjacent to the DREZ (Fig. 1B), but its expression is down-regulated in the dorsal spinal cord at E13.5 when many collaterals have entered the mantle layer. Third, repulsive netrin-1 receptor Unc5c is expressed in the DRG neurons during development.These observations motivated us to explore whether netrin-1/Unc5c signaling contributes to DRG axonal guidance. We used cell and tissue cultures combined with tissues from netrin-1-deficient mice. We clearly showed that netrin-1 exerts a chemorepulsive activity toward developing DRG axons and that the ventral spinal cord-derived repulsive activity depends on netrin-1 in vitro.⁸ Additional evidence for a chemorepulsive role of netrin-1 came from the observation of DRG axonal trajectories in netrin-1-deficient mice.^7,8 In netrin-1-deficient embryos at E10, we showed that some DRG axons became misoriented toward the ventral spinal cord, probably because of the absence of netrin-1 proteins in the ventral spinal cord (Fig. 1A). In addition, at E12.5 when DRG axons grow to the marginal zone of the spinal cord longitudinally to form the dorsal funiculus, the dorsal funiculus is disorganized in netrin-1-deficient embryos, because in the absence of netrin-1 DRG axons are not waiting for invading the dorsal mantle layer adjacent to the dorsal funiculus (Fig. 1B). Gain-of-function experiments further confirmed the repulsive activity of netrin-1 toward DRG axons (Fig. 1C). These lines of evidence lead us to the conclusion that dorsally derived netrin-1 plays an important role in providing the ‘waiting period’ for extension of collaterals from sensory afferents and that ventrally derived netrin-1 prevents sensory axons from misorienting themselves toward the ventral spinal cord.At later developmental stages (E13.5), DRG axons still possess a weak responsiveness to the chemorepulsive activity of netrin-1 in vitro.⁸ In addition, both postnatal and adult DRG neurons respond to netrin-1-induced axon inhibition.⁹ Consistent with these results, DRG neurons at not only later developmental stages (E13.5) but also postnatal stages express the repulsion-mediating netrin-1 receptor Unc5c.^8,9Generally, lesioning of the dorsal column projection of sensory axons results in a complete lack of regeneration. The possible explanation for the complete lack of regeneration is that the environment, the lesion site itself and/or oligodendrocytes adjacent to the lesion, may be non-permissive for regenerating axons.¹⁰ Sema3A and chondroitin sulfate proteoglycans (CSPGs) are candidates as major inhibitors of sensory axonal regeneration in the spinal cord, because they are expressed in the lesion site and can inhibit DRG axonal growth in vitro.^3,11–14 Recently, Kaneko et al. showed that a selective inhibitor of Sema3A also enhances axonal regeneration and functional recovery in a subpopulation of sensory neurons after lesioning of the dorsal column.¹² More recently, McMahon''s group clearly demonstrated that enzymatic degradation of CSPGs on the dorsal column lesion of the spinal cord promotes sensory axonal regeneration and functional recovery.^13,14 Although these treatments greatly improved functional recovery, complete sensory axonal growth and functional recovery have not been yet achieved after the spinal cord injury. To promote further recovery of sensory axonal regeneration in the CNS, we should focus on other candidate inhibitors of CNS injury sites.Following spinal cord injury, the expression of the attraction- mediating netrin-1 receptor DCC decreases, while the expression level of the repulsive receptor Unc5c returns to normal.¹⁵ Levels of netrin-1 expression also stay unchanged in neurons and oligodendrocytes adjacent to the lesion site. Together with the in vitro evidence described above, these data strongly suggest a possible role for netrin-1 as a novel inhibitor of CNS myelin for regenerating DRG axons in the dorsal column-lesioned spinal cord. Further studies will be required to show directly the functional recovery of sensory axons in the spinal cord by perturbation of netrin-1 in and around the lesion site after spinal cord injury.     

End-of-life practices in Danish ICUs: development and validation of a questionnaire

ABSTRACT: BACKGROUND: Practices for withholding or withdrawing therapy vary according to professional, cultural and religious differences. No Danish-validated questionnaire examining withholding and withdrawing practices exists, thus the aim of this study was to develop and validate a questionnaire for surveying the views of intensive care nurses, intensivists, and primary physicians regarding collaboration and other aspects of withholding and withdrawing therapy in the ICU. METHODS: A questionnaire was developed on the basis of literature, focus group interviews with intensive care nurses and intensivists, and individual interviews with primary physicians. The questionnaire was validated in the following 3 phases: a qualitative test with 17 participants; a quantitative pilot test with 60 participants; and a survey with 776 participants. The validation process included tests for face and content validity (by interviewing participants in the qualitative part of the pilot study), reliability (by assessing the distribution of responses within the individual response categories), agreement (by conducting a test-retest, evaluated by paired analyses), known groups' validity (as a surrogate test for responsiveness, by comparing two ICUs with a known difference in end-of-life practices), floor and ceiling effect, and missing data. RESULTS: Face and content validity were assessed as good by the participants in the qualitative pilot test; all considered the questions relevant and none of the participants found areas lacking. Almost all response categories were used by the participants, thus demonstrating the questionnaires ability to distinguish between different respondents, agreement was fair (the average test-retest agreement for the Likert scale responses was 0.54 (weighted kappa; range, 0.25-0.73), and known groups' validity was proved by finding significant differences in level of satisfaction with interdisciplinary collaboration and in experiences of withdrawal decisions being unnecessary postponed. Floor and ceiling effect was in accordance with other questionnaires, and missing data was limited to a range of 0-7% for all questions. CONCLUSIONS: The validation showed good and fair areas of validity of the questionnaire. The questionnaire is considered a useful tool to assess the perceptions of collaboration and other aspects of withholding and withdrawing therapy practices in Danish ICUs amongst nurses, intensivists, and primary physicians.     

Inhibitory control of sensory gating in a computer model of the CA3 region of the hippocampus

 A model of the CA3 region of the hippocampus was used to simulate the P50 auditory-evoked potential response to repeated stimuli in order to study the neuronal circuits involved in a sensory-processing deficit associated with schizophrenia. Normal subjects have a reduced P50 auditory-evoked potential amplitude in response to the second of two paired auditory click stimuli spaced 0.5 s apart. However, schizophrenic patients do not gate or reduce their response to the second click. They have equal auditory-evoked response amplitudes to both clicks. When schizophrenic patients were medicated with traditional neuroleptics, the evoked potential amplitude to both clicks increased, but gating of the second response was not restored or improved. Animal studies suggest a role for septohippocampal cholinergic activity in sensory gating. We used a computational model of this system in order to study the relative contributions of local processing and afferent activity in sensory gating. We first compared the effect of information representation as average firing rate to information representation as cell assemblies in order to evaluate the best method to represent the response of hippocampal neurons to the auditory click. We then studied the effects of nicotinic cholinergic input on the response of the network and the effect of GABA_B receptor activation on the ability of the local network to suppress the test response. The results of our model showed that nicotinic cholinergic input from the septum to the hippocampus can control the flow of sensory information from the cortex into the hippocampus. In addition, postsynaptic GABA_B receptor activation was not sufficient to suppress the test response when the interstimulus interval was 500 ms. However, presynaptic GABA_B receptor activity may be responsible for the suppression of the test response at this interstimulus interval. Received: 3 December 2001 / Accepted: 23 October 2002 / Published online: 28 February 2003 Correspondence to: K. A. Moxon (e-mail: karen.moxon@drexel.edu, Tel.:+1-215-8951959, Fax: +1-215-8954983) Supported by USPHS, MH01245, MH58414, MH-50787, MH-01121, and research grants from the Department of Veterans Affairs and the National Alliance for Research on Schizophrenia and Depression.     

Structured skills training for adults with ADHD in an outpatient psychiatric context: an open feasibility trial

The aim of the current study was to evaluate the feasibility, acceptability, and effectiveness of Dialectical Behavioral Therapy-based skills training groups for adults with ADHD in an outpatient psychiatric context. Furthermore, the purpose was to analyze the impact of clinical characteristics on the effect and attrition. Ninety-eight adults (out of 102) with ADHD were allocated to the treatment. Self-rating scales were administered as baseline before the first session (T1), post-treatment (T2), and at 3-month follow-up (T3). Approximately 80 % (74 individuals) attended at least two-thirds of the sessions. Treatment satisfaction was good. ADHD symptoms and ADHD-related functional impairment in every-day life were reduced. Well-being, ability to be mindful, acceptance of emotions and quality of life were increased. The results were stable at 3-month follow-up. None of the predictors, i.e., age, comorbidity, ADHD medication status, IQ-level, treatment credibility, or functional impairment at the beginning of treatment, significantly predicted treatment outcome (change in ADHD symptoms from T1 to T2). Likewise, none of the predictors, i.e., irritability/aggression, comorbidity, and functional impairment, were significantly associated with attrition. Due to the difficulties in predicting treatment outcome, as well as attrition, based on clinical characteristics, broad inclusion criteria should be applied.     

Tectonics of a K+ channel: The importance of the N-terminus for channel gating

The small K⁺ channel Kcv represents the pore module of complex potassium channels. It was found that its gating can be modified by sensor domains, which are N-terminally coupled to the pore. This implies that the short N-terminus of the channel can transmit conformational changes from upstream sensors to the channel gates. To understand the functional role of the N-terminus in the context of the entire channel protein, we apply combinatorial screening of the mechanical coupling and long-range interactions in the Kcv potassium channel by reduced molecular models. The dynamics and mechanical connections in the channel complex show that the N-terminus is indeed mechanically connected to the pore domain. This includes a long rang coupling to the pore and the inner and outer transmembrane domains. Since the latter domains host the two gates of the channel, the data support the hypothesis that mechanical perturbation of the N-terminus can be transmitted to the channel gates. This effect is solely determined by the topology of the channel; sequence details only have an implicit effect on the coarse-grained dynamics via the fold and not through biochemical details at a smaller scale. This observation has important implications for engineering of synthetic channels on the basis of a K⁺ channel pore.     

Kindling of the limbic structures with a shortened interstimulus interval

We investigated the possibility to produce hippocampal or amygdala kindling syndrome in rabbits which had been electrically stimulated at a fixed interval between stimuli at 5 min. Animals were prepared with chronically implanted electrodes (neocortex, hippocampus, amygdala, nucleus caudatus). The initial stimuli produced only localized effect, but repeated applications of the stimuli progressively increased the seizure activity resulting in generalized kindled convulsions after 2-4 h period. At the first stage generalized seizures were followed by long lasting refractory period, but at the end of the procedure almost all stimuli evoke major motor seizures and recurrent widely spread electrographic epileptic changes. The most noteworthy findings emerging from this study is the inhibition of postictal seizure inhibition period. This effect was independent of whether stimulated the electrode was positioned in the hippocampus or amygdala, but the hippocampal formation occupied the central position for the once and propagation of the seizure activity in all cases. When established this syndrome persisted without any attenuation for some weeks. It was concluded that this model of rapid development of kindling syndrome is useful for investigation of the nature of epilepsy and postictal seizure inhibition.     

Project DyAdd: Fatty acids and cognition in adults with dyslexia, ADHD, or both

Both attention deficit hyperactivity disorder (ADHD) and dyslexia are suggested to co-occur with altered fatty acid (FA) metabolism, but it is unknown how FAs are associated with the cognitive domains that characterize these disorders. In the project DyAdd, we investigated the associations between FAs in serum phospholipids and phonological processing, reading, spelling, arithmetic, executive functions, and attention. Healthy controls (n=36), adults with ADHD (n=26), dyslexia (n=36), or both (n=9) were included in the study. FAs included saturated, monounsaturated, total polyunsaturated, n-3, and n-6 FAs, together with n-6/n-3, AA/EPA, and LA/ALA ratios. When all the study subjects were included in the analyses, especially polyunsaturated FAs (PUFAs) were positively associated with cognition, but reading was least associated with FAs. These associations were modulated by gender, intelligence, n-3 PUFA intake, and group. Accordingly, within the ADHD group, only few associations emerged with PUFAs, n-6 PUFAs, and cognitive domains, whereas in the dyslexia group the more prevalent associations appeared with PUFAs and n-3 PUFAs.     

The development of a culture specific screening questionnaire NSRQ-20 for use in psychiatric epidemiology: A preliminary report

A list of ten culture-specific symptoms frequently volunteered by Nigerian patients with Minor Psychiatric Disorders was added to the twenty items of the SRQ-20. The resultant 30-item questionnaire (SRQ-30) discriminated very well between a sample of new non-psychotic psychiatric referrals and a sample of subjects with very low probability of caseness (relatives of the new psychiatric referrals). Elimination of items of the SRQ-30 which poorly discriminated between the sample of psychiatric referrals and a matched sample of general hospital patients (ten items) produced the Nigerian version of the SRQ-20 (NSRQ-20) whose sensitivity is shown to be higher than that of the SRQ-30. Further validation study and future research trends on the NSRQ-20 are suggested.     

Discriminating between ADHD adults and controls using independent ERP components and a support vector machine: a validation study

Background

There are numerous event-related potential (ERP) studies in relation to attention-deficit hyperactivity disorder (ADHD), and a substantial number of ERP correlates of the disorder have been identified. However, most of the studies are limited to group differences in children. Independent component analysis (ICA) separates a set of mixed event-related potentials into a corresponding set of statistically independent source signals, which are likely to represent different functional processes. Using a support vector machine (SVM), a classification method originating from machine learning, this study aimed at investigating the use of such independent ERP components in differentiating adult ADHD patients from non-clinical controls by selecting a most informative feature set. A second aim was to validate the predictive power of the SVM classifier by means of an independent ADHD sample recruited at a different laboratory.

Methods

Two groups of age-matched adults (75 ADHD, 75 controls) performed a visual two stimulus go/no-go task. ERP responses were decomposed into independent components, and a selected set of independent ERP component features was used for SVM classification.

Results

Using a 10-fold cross-validation approach, classification accuracy was 91%. Predictive power of the SVM classifier was verified on the basis of the independent ADHD sample (17 ADHD patients), resulting in a classification accuracy of 94%. The latency and amplitude measures which in combination differentiated best between ADHD patients and non-clinical subjects primarily originated from independent components associated with inhibitory and other executive operations.

Conclusions

This study shows that ERPs can substantially contribute to the diagnosis of ADHD when combined with up-to-date methods.