A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment.

Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.

Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder.

BACKGROUND: Atomoxetine, a highly selective noradrenaline reuptake inhibitor (SNRI), shows efficacy in the treatment of attention-deficit/hyperactivity disorder (ADHD). Compared with psychostimulants, atomoxetine has a distinct mode of brain action and potentially lower addictive potential. Studies have yet to assess whether atomoxetine improves cognition following a single oral dose in ADHD. METHODS: Twenty-two adults with DSM-IV ADHD were administered a single oral dose of atomoxetine (60 mg) in a placebo-controlled double-blind crossover design. Cognitive effects were assessed using stop-signal, sustained attention, spatial working memory, and set-shifting paradigms. Normative cognitive data from 20 healthy volunteers were collected for comparison. RESULTS: The ADHD patients under placebo conditions showed response inhibition and working memory deficits compared with healthy volunteers. Atomoxetine treatment in the ADHD patients was associated with shorter stop-signal reaction times and lower numbers of commission errors on the sustained attention task. CONCLUSIONS: Atomoxetine improved inhibitory control, most likely via noradrenergically mediated augmentation of prefrontal cortex function. These results have implications for understanding the mechanisms by which atomoxetine exerts beneficial clinical effects and suggest novel treatment directions for other disorders of impulsivity.

Association between response inhibition and working memory in adult ADHD: a link to right frontal cortex pathology?

BACKGROUND: We sought to assess the relationship between response inhibition and working memory in adult patients with attention-deficit/hyperactivity disorder (ADHD) and neurosurgical patients with frontal lobe damage. METHODS: The stop-signal reaction time (SSRT) test and a spatial working memory (SWM) task were administered to 20 adult patients with ADHD and a group of matched controls. The same tasks were administered to 21 patients with lesions to right frontal cortex and 19 patients with left frontal lesions. RESULTS: The SSRT test, but not choice reaction time, was significantly associated with search errors on the SWM task in both the adult ADHD and right frontal patients. In the right frontal patients, impaired performance on both variables was correlated with the volume of damage to the inferior frontal gyrus. CONCLUSIONS: Response inhibition and working memory impairments in ADHD may stem from a common pathologic process rather than being distinct deficits. Such pathology could relate to right frontal-cortex abnormalities in ADHD, consistent with prior reports, as well as with the demonstration here of a significant association between SSRT and SWM in right frontal patients.

Lack of deleterious effects of buspirone on cognition in healthy male volunteers.

Buspirone is a serotonin 5-HT(1A) receptor agonist licensed for the treatment of anxiety. Other anxiolytic drugs such as benzodiazepines show significant sedative and other unwanted effects on cognition. Studies to date have yet to investigate cognitive effects of buspirone using well-validated computerized tests. The aim of this study was to assess acute subjective and cognitive effects of buspirone in healthy volunteers. Sixty healthy male volunteers received 20 mg buspirone, 30 mg buspirone, or placebo per os in a double-blind parallel groups design (N=20 per group). Subjective ratings (visual analogue scales) were completed at baseline, and at 1.5 and 3.5 hours post-capsule. Cognitive assessment was undertaken between 1.5 and 3.5 hours post-capsule, including tests of memory, executive planning, impulse control, decision making and cognitive flexibility. The 30 mg buspirone group showed significantly higher subjective ratings of contentedness 3.5 hours after capsule relative to placebo. Treatment and placebo groups did not differ significantly on cognitive measures. In contrast to benzodiazepines, the anxiolytic buspirone appears to lack detectable deleterious effects on cognition when administered acutely at clinically meaningful doses. Future research directions are discussed in relation to acute and chronic studies in neuropsychiatric populations.

Questionnaire ratings of attention-deficit/hyperactivity disorder (ADHD) in adults are associated with spatial working memory.

OBJECTIVE: Data related to brain function may have the potential to improve the reliability and validity of assessments for the aetiologically and clinically heterogeneous syndrome of attention-deficit/hyperactivity disorder (ADHD). This study investigated associations between questionnaire assessments of behavioural features of adults with ADHD and an aspect of neurocognitive performance which has been reported to be impaired in adults with ADHD. METHODS: Fifty-nine adult patients with a DSM-IV diagnosis of ADHD, and their informants, completed questionnaires related to aspects of severity of ADHD. Associations were examined between questionnaire ratings and performance on a computer-administered task of spatial working memory (SWM). RESULTS: Correlations between ratings of ADHD and SWM indicated moderate but significant correlations for patients' ratings, but not for informants' ratings. Also, patients who reported a past history of 'self-harm' (N=33) had a significantly worse mean performance on both measures of SWM (p=0.004, 0.003). CONCLUSIONS: The results indicate that aspects of impulsivity, i.e. self-ratings of 'emotive' behaviour (involving rapid response to stimuli and marked reactivity of mood) and of past 'self-harm', show relatively strong associations with SWM performance in adults selected on the basis of an ADHD diagnosis. A profile of neurocognitive performances may have a role in the assessment of ADHD.

Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder.

RATIONALE: Features of childhood attention-deficit/hyperactivity disorder (ADHD) often persist into adulthood. It has been shown that adult ADHD is associated with various neurocognitive deficits, including impairments in spatial working memory (SWM) and attention. It is not known whether these deficits are ameliorated by methylphenidate in adult ADHD. OBJECTIVES: The aim of this study was to evaluate the neurocognitive effects of a single dose of methylphenidate on SWM, visual memory, spatial span and sustained attention in adult ADHD. METHODS: Twenty-four adult patients, recruited from a specialised clinic for the assessment of adult ADHD, were entered into a double-blind, randomised, placebo-controlled crossover study using a single 30 mg dose of methylphenidate. RESULTS: Eighteen patients met DSM-IV criteria for adult ADHD. Methylphenidate resulted in an improvement in SWM performance and sustained attention, together with a speeding in response time, in these patients. Six patients with attentional difficulties, who did not meet a DSM-IV diagnosis of ADHD, showed a different pattern of response to methylphenidate compared to the ADHD group. For the combined group, moderate correlations were shown between childhood ratings of ADHD (both self-reported and informant ratings) and response to methylphenidate on the SWM task. CONCLUSIONS: Adults with ADHD had a similar neurocognitive response to methylphenidate to that previously reported for childhood ADHD. Our results provide further support for the validity of the ADHD syndrome as defined by DSM-IV and indicate possible neurocognitive substrates for clinical improvement with chronic methylphenidate.

Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder.

BACKGROUND: Modafinil, a novel cognitive enhancer, has a clinical profile similar to conventional stimulants such as methylphenidate, despite a seemingly different mechanism of action. Modafinil selectively improves neuropsychological task performance in healthy volunteers, possibly through improved inhibitory control. We examined whether modafinil induced similar improvements in adults with attention-deficit/hyperactivity disorder. METHODS: Twenty patients with a DSM-IV diagnosis of attention-deficit/hyperactivity disorder were entered into a double-blind, randomized, placebo-controlled crossover study using a single 200 mg dose of modafinil. RESULTS: Modafinil produced a similar pattern of cognitive enhancement to that observed in healthy adults, with improvements on tests of short-term memory span, visual memory, spatial planning, and stop-signal motor inhibition. On several measures, increased accuracy was accompanied by slowed response latency. This alteration in the speed-accuracy trade-off may indicate that modafinil increases the ability to "reflect" on problems coupled with decreased impulsive responding. Improvements were also seen in sustained attention, which was unaffected in healthy subjects. CONCLUSIONS: If these benefits are shown to be maintained with chronic administration, modafinil may have potential as an important therapy for attention-deficit/hyperactivity disorder with a similar effect to stimulants such as methylphenidate in improving stop-signal response inhibition but without the side effects commonly experienced with amphetamine-like drugs.

Cognitive enhancing effects of modafinil in healthy volunteers.

RATIONALE: Modafinil, a novel wake-promoting agent, has been shown to have a similar clinical profile to that of conventional stimulants such as methylphenidate. We were therefore interested in assessing whether modafinil, with its unique pharmacological mode of action, might offer similar potential as a cognitive enhancer, without the side effects commonly experienced with amphetamine-like drugs. OBJECTIVES: The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests. METHODS: Sixty healthy young adult male volunteers received either a single oral dose of placebo, or 100 mg or 200 mg modafinil prior to performing a variety of tasks designed to test memory and attention. A randomised double-blind, between-subjects design was used. RESULTS: Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects were not clearly dose dependent, except for those seen with the stop-signal paradigm. In contrast to previous findings with methylphenidate, there were no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. Additionally, no effects on paired associates learning were identified. CONCLUSIONS: These data indicate that modafinil selectively improves neuropsychological task performance. This improvement may be attributable to an enhanced ability to inhibit pre-potent responses. This effect appears to reduce impulsive responding, suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder.

Relative lack of cognitive effects of methylphenidate in elderly male volunteers.

RATIONALE: Methylphenidate, a dopaminergic and noradrenergic reuptake inhibitor, has been shown in young, healthy adult volunteers to produce pronounced effects on working memory and sustained attention. We were interested in assessing whether similar improvements could be conferred upon elderly volunteers in order to gain a more complete understanding of the effects of age on monoaminergic manipulations of working memory and attention, as well as to explore the potential for pharmacological intervention in attention and executive dysfunction disorders in this age group. OBJECTIVES: The main aim of the study was to characterise the dose-related effects of methylphenidate on a range of neuropsychological functions in elderly healthy volunteers. METHODS: Sixty healthy elderly adult male volunteers received either a single oral dose of placebo, 20 mg or 40 mg methylphenidate prior to performing a variety of tasks designed to assess memory, attention and executive function. A randomised double-blind, between-subjects design was used. RESULTS: Methylphenidate had significant cardiovascular and subjective effects. However, unlike in younger volunteers, no significant effects of drug on working memory (spatial span and spatial working memory), response inhibition (stop-signal) or sustained attention (rapid visual information processing) were seen. Subtle effects on latency similar to those in younger volunteers were identified: both doses of methylphenidate resulted in a slowing in response time during set-shifting and decision-making. CONCLUSIONS: The results of this study demonstrate that, in elderly subjects, the cognitive effects of methylphenidate are grossly attenuated and distinct from the profile previously described in younger volunteers. It is suggested that methylphenidate may not be appropriate as a pharmacological intervention in elderly patient groups, such as those reporting age-related cognitive decline.

Associations of the severity of depressive disorders in women with psychogenic low weight.

BACKGROUND: Depressive disorders are common in patients with anorexia nervosa (AN). Although depression with AN has been considered to be mainly secondary to the features of AN, other characteristics of such patients may also be causal, as personality disorders (PDs) often occur with AN and there are indications that PDs are causal factors for some depressive disorders. This study examined associations of the severity of depressive disorders in patients with low weight and a history of full or partial AN, to determine which characteristics of patients with AN are candidates as causal factors for depression in this context. METHODS: 66 patients of a psychiatric 'low-weight' clinic completed self-report questionnaires. These patients presented with a mean body mass index (BMI) of 17.0 (S.D. 1.4) and their mean lowest BMI after the age of 16 had been 15.2 (S.D. 1.3). RESULTS: Beck Depression Inventory (BDI) ratings were significantly associated with a range of eating disorder features (including age at presentation but not BMI) and with characteristics of a range of DSM-III-R PDs. LIMITATIONS: BDI ratings do not reflect clinical heterogeneity of depressive disorders, while self-report data for PD psychopathology can be subject to confounding variables. CONCLUSIONS: The results suggest that, first, features of AN (but not the degree of weight loss), and, second, psychopathology related to some features of all three DSM-III-R PD clusters may have causal roles in relation to depressive disorders in patients with AN and its variants. The findings indicate the need to consider a range of features of PDs in the management of patients with depression and AN.

Characteristics of neuronal lipofuscin in the superior temporal gyrus in Alzheimer's disease do not differ from non-diseased controls: a comparison with disease-related changes in the superior frontal gyrus.

Neuronal lipofuscin characteristics in the superior temporal gyrus from 21 patients with Alzheimer's disease (AD) and from 18 age-matched non-diseased subjects were compared with previously reported findings from the superior frontal gyrus. A discriminant function analysis of lipofuscin characteristics in the superior temporal gyrus did not provide a significant predictive level for cases whose diagnoses were correctly classified (56.4%, P=0.63). In contrast, AD-related decrease in the number of smaller lipofuscin regions in the neurons of the frontal gyrus was confirmed, and the same analysis of lipofuscin characteristics in this region gave a significant predictive level for membership of the AD group of 86.6% (P<0.001). The findings indicate that changes in neuronal lipofuscin related to AD, which may reflect an increased rate of lipofuscin formation, show differences between neocortical regions. This study provides additional information on the distribution of neuropathological characteristics in AD.

Impaired visual discrimination learning in anorexia nervosa.

The primate dopamine system is involved in appetitively motivated behaviours, including certain forms of learning, for example, visual discrimination learning. Furthermore, food restriction in animals and anorexia in humans is associated with impaired dopamine signaling. Based on this, we hypothesized that patients with anorexia nervosa (AN) would show a deficit in visual discrimination learning. In a dynamic categorization task involving the learning of a series of two-alternative forced-choice visual discriminations, conceptually identical to one shown to activate dopamine neurons in primates, and sensitive to dopaminergic manipulations in humans, patients with AN showed a deficit in learning that was most pronounced in the early stages of acquisition. In contrast, AN showed spared performance on a pattern recognition memory test sensitive to medial temporal lobe lesions, but insensitive to dopaminergic manipulations. We conclude that impaired appetitive function in patients with AN extends to include deficits in visual discrimination learning, and that this deficit represents indirect evidence for altered dopaminergic neurotransmission in AN.

Impulsivity in patients with borderline personality disorder.

This study investigated features of impulsivity in patients with borderline personality disorder (BPD) using the self-report Attention-Deficit Scales for Adults (ADSA) and computer-administered neurocognitive tasks. Forty-one patients with DSM-III-R BPD and 35 nonclinical control subjects were assessed by the ADSA, the National Adult Reading Test, and two computerized tasks mediated by the frontal lobes. Mean scores for seven ADSA scales (six of which relate to aspects of impulsivity) were significantly higher in the patient group compared with the control group. Also, the ADSA ratings for impaired coordination were increased in the BPD patients. The findings indicate that a range of aspects of impulsivity, as well as impaired coordination, are associated with patients selected on the basis of BPD. Also, in the patient group, but not in the control group, associations of the neurocognitive tasks indicated that, first, performance on a planning task related to dorsolateral frontal lobe functioning is correlated with aspects of impulsivity reflected by ADSA scale III ratings (involving disorganisation and lack of perseverance) and, second, performance on a decision-making task related to orbitofrontal functioning is correlated with ratings of impaired coordination. Further work is needed to establish the specificity of the findings.