Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors

Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were rested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 mu g/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggestinga primary involvement of the 5-HT1A receptor in the observed defecit. Based on physiological and pharmacological data,we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

The effects of task complexity and practice on dual-task interference in visuospatial working memory

Although the n-back task has been widely applied to neuroimagery investigations of working memory (WM), the role of practice effects on behavioural performance of this task has not yet been investigated. The current study aimed to investigate the effects of task complexity and familiarity on the n-back task. Seventy-seven participants (39 male, 38 female) completed a visuospatial n-back task four times, twice in two testing sessions separated by a week. Participants were required to remember either the first, second or third (n-back) most recent letter positions in a continuous sequence and to indicate whether the current item matched or did not match the remembered position. A control task, with no working memory requirements required participants to match to a predetermined stimulus position. In both testing sessions, reaction time (RT) and error rate increased with increasing WM load. An exponential slope for RTs in the first session indicated dual-task interference at the 3-back level. However, a linear slope in the second session indicated a reduction of dual-task interference. Attenuation of interference in the second session suggested a reduction in executive demands of the task with practice. This suggested that practice effects occur within the n-back ask and need to be controlled for in future neuroimagery research using the task.

Attention deficit disorder: not just for children

Attention deficit/hyperactivity disorder (ADHD) has long been described in children who demonstrate developmentally inappropriate symptoms of inattention, impulsivity and motor restlessness. In adults, symptoms are known to persist and the validity of adult ADHD as an entity is now recognized. There is an associated high proportion of other serious psychiatric comorbidities, especially substance abuse, mood and anxiety disorders. Advances have been made into the aetiology and management of ADHD. Many of these focus on the dopamine and noradrenaline pathways.

An n-of-1 trial service in clinical practice: Testing the effectiveness of stimulants for attention-deficit/hyperactivity disorder

OBJECTIVE. We sought to describe the clinical use of n-of-1 trials for attention-deficit/hyperactivity disorder in publicly and privately funded family and specialized pediatric practice in Australia. METHODS. We used a within-patient randomized, double-blind, crossover comparison of stimulant (dexamphetamine or methylphenidate) versus placebo or alternative stimulant using 3 pairs of treatment periods. Trials were conducted from a central location using mail and telephone communication, with local supervision by the patients' clinicians. PATIENTS. Our study population included children with clinically diagnosed attention-deficit/ hyperactivity disorder who were aged 5 to 16 years and previously stabilized on an optimal dose of stimulant. They were selected because treatment effectiveness was uncertain. MAIN OUTCOME MEASURES. Our measures included number of patients recruited, number of doctors who used the service, geographic spread, completion rates, response rate, and post-n-of-1 trial decisions. RESULTS. Forty-five doctors across Australia requested 108 n-of-1 trials, of which 86 were completed. In 69 drug-versus-placebo comparisons, 29 children responded better to stimulant than placebo. Immediately posttrial, 19 of 25 drug-versus-placebo responders stayed on the same stimulant, and 13 of 24 nonresponders ceased or switched stimulants. In 40 of 63 for which data were available, posttrial management was consistent with the trial results. For all types of n-of-1 trials, management changed for 28 of 64 children for whom information was available. DISCUSSION. Attention-deficit/hyperactivity disorder n-of-1 trials can be implemented successfully by mail and telephone communication. This type of trial can be valuable in clarifying treatment effect when it is uncertain, and in this series, they had a noticeable impact on short-term management.

Responding to interpersonal and physically provoking situations in classrooms: emotional intensity in children with attention deficit hyperactivity disorder

The present research investigated the emotional functioning of children with and without Attention Deficit Hyperactivity Disorder (ADHD), in order to examine the relationships between emotional intensity and classroom-based responses to physically and interpersonally provoking situations. Seventy children (35 with ADHD and 35 without ADHD) in Years 3–8 participated and were matched on age, gender, grade, and school class. Each child was observed individually in the classroom over two 20-min periods. The Responses to Interpersonal and Physically Provoking Situations Observation Schedule was used to record the frequency and severity of responses and the triggers for these during the observational periods. Children later rated their emotional intensity in response to hypothetical scenarios on the Emotional Intensity Scale for Children. Results revealed children with ADHD displayed significantly more frequent and severe challenging and solitary off-task behaviours, and significantly more frequent vocalisations and severe interactional off-task behaviours. For triggers, environmental and teacher-initiated distractions were significantly more frequently observed in children with ADHD. There were no differences in ratings of emotional intensity between children with and without ADHD, although a number of significant and meaningful correlations were observed between positive emotional intensity scores and responses and triggers.

Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with Attention Deficit/Hyperactivity Disorder

Objective To compare the efficacy and safety of two methylphenidate (MPH) formulations—once-daily modified-release MPH (EqXL, Equasym™ XL) and twice-daily immediate-release methylphenidate (MPH-IR, Ritalin®)—and placebo in children with Attention Deficit/Hyperactivity Disorder (ADHD). Methods Children aged 6–12 years on a stable dose of MPH were randomized into a double-blind, three-arm, parallel-group, multi-center study and received 3 weeks of EqXL (20, 40, or 60 mg qd), MPH-IR (10, 20, or 30 mg bid) or placebo. Non-inferiority of EqXL to MPH-IR was assessed by the difference in the inattention/overactivity component of the overall teacher’s IOWA Conners’ Rating Scale on the last week of treatment (per protocol population). Safety was monitored by adverse events, laboratory parameters, vital signs, physical exam, and a Side Effect Rating Scale. Results The lower 97.5% confidence interval bound of the difference between MPH groups fell above the non-inferiority margin (−1.5 points) not only during the last week of treatment but during all three treatment weeks. Both MPH-treatment groups experienced superior benefit when compared to placebo during all treatment weeks (P < 0.001). All treatments were well tolerated. Conclusions EqXL given once-daily was non-inferior to MPH-IR given twice-daily. Both treatments were superior to placebo in reducing ADHD symptoms.

Attention vs. emotion: Affective learning and the startle reflex

The eye-blink startle reflex can be modulated by attentional and emotional processes. The reflex is facilitated during stimuli that engage attention. A linear pattern of emotional modulation has also been consistently demonstrated: the reflex is facilitated during unpleasant stimuli and attenuated during pleasant stimuli. However, during anticipation of pleasant or unpleasant stimuli it is unclear whether emotion or attention drives startle reflex modulation. This study used a differential learning procedure to investigate whether startle modulation during anticipation of a salient stimulus reflected emotional or attentional processes. In acquisition, a CS+ was paired with a pleasant or unpleasant US and a CS- was presented alone. In extinction, blink startle magnitude was measured during CS+ and CS-. Post-acquisition valence ratings and affective priming showed that CS+ had acquired the same affective value as the pleasant or unpleasant US with which it was paired. No differences in modulation of blink startle reflexes during pleasant CS+ and unpleasant CS+ were found throughout extinction. Blink startle facilitation occurred during CS+ but not CS- across the first third of extinction. Thus, attentional rather than emotional processes appeared to facilitate blink startle during anticipation of salient stimuli.

Progressive loss of expressive language in a journalist: What news for dementia?

A 77-year-old man with 8 year progressive language deterioration in the face of grossly intact memory was followed. No acute or chronic physiological or psychological event was associated with symptom onset. CT revealed small left basal ganglia infarct. Mild atrophy, no lacunar infarcts, mild diffuse periventricular changes registered on MRI. Gait normal but slow. Speech hesitant and sparse. Affect euthymic; neurobehavioral disturbance absent. MMSE 26/30; clock incorrect, concrete. Neuropsychological testing revealed simple attention intact; complex attention, processing speed impaired. Visuospatial copying and delayed recall of copy average with some perseveration. Apraxia absent. Recall mildly impaired. Mild deficits in planning, organization apparent. Patient severely aphasic, dysarthric without paraphasias. Repetition of automatic speech, recitation moderately impaired; prosody intact. Understanding of written language, nonverbal communication abilities, intact. Frontal release signs developed over last 12 months. Repeated cognitive testing revealed mild deterioration across all domains with significant further decrease in expressive, receptive language. Neurobehavioral changes remain absent to date; he remains interested, engaged and independent in basic ADLs. Speech completely deteriorated; gait and movements appreciably slowed. Although signs of frontal/executive dysfunction present, lack of behavioral abnormalities, psychiatric disturbance, personality change argue against focal or progressive frontal impairment or dementia. Relative intactness of memory and comprehension argue against Alzheimer’s disease. Lack of findings on neuroimaging argue against CVA or tumor. It is possible that the small basal ganglia infarct has resulted in a mild lateral prefrontal syndrome. However, the absence of depression as well as the relatively circumscribed language problem suggests otherwise. The progressive, severe nature of language impairments, with relatively minor impairments in attention and memory, argues for a possible diagnosis of primary progressive aphasia.