Natalia del Campo

Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives

Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors associated with underlying dysregulation of frontostriatal circuitry. Central to neurobiological models of OCD is the orbitofrontal cortex, a neural region that facilitates behavioral flexibility after negative feedback (reversal learning). We identified abnormally reduced activation of several cortical regions, including the lateral orbitofrontal cortex, during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype for this disorder.

The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder.

Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified. Herein, we review and discuss the present state of knowledge regarding the roles of dopamine (DA) and noradrenaline in the regulation of corticostriatal circuits, with a focus on the molecular neuroimaging literature (both in ADHD patients and in healthy subjects). Recent positron emission tomography evidence has highlighted the utility of quantifying DA markers, at baseline or following drug administration, in striatal subregions governed by differential cortical connectivity. This approach opens the possibility of characterizing the neurobiological underpinnings of ADHD (and associated cognitive dysfunction) and its treatment by targeting specific neural circuits. It is anticipated that the application of refined and novel positron emission tomography methodology will help to disentangle the overlapping and dissociable contributions of DA and noradrenaline in the prefrontal cortex, thereby aiding our understanding of ADHD and facilitating new treatments.

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.

Atomoxetine Modulates Right Inferior Frontal Activation During Inhibitory Control: A Pharmacological Functional Magnetic Resonance Imaging Study

BACKGROUND Atomoxetine, a selective noradrenaline reuptake inhibitor (SNRI) licensed for the treatment of attention-deficit/hyperactivity disorder (ADHD), has been shown to improve response inhibition in animals, healthy volunteers, and adult patients. However, the mechanisms by which atomoxetine improves inhibitory control have yet to be determined. METHODS The effects of atomoxetine (40 mg) were measured with a stop-signal functional magnetic resonance imaging (fMRI) paradigm in 19 healthy volunteers, in a within-subject, double-blind, placebo-controlled design. RESULTS Atomoxetine improved inhibitory control and increased activation in the right inferior frontal gyrus when volunteers attempted to inhibit their responses (irrespective of success). Plasma levels of drug correlated significantly with right inferior frontal gyrus activation only during successful inhibition. CONCLUSIONS These results show that atomoxetine exerts its beneficial effects on inhibitory control via modulation of right inferior frontal function, with implications for understanding and treating inhibitory dysfunction of ADHD and other disorders.

Grey matter abnormalities in trichotillomania: morphometric magnetic resonance imaging study

Background Trichotillomania (repetitive hair-pulling) is an Axis I psychiatric disorder whose neurobiological basis is incompletely understood. Whole-brain trichotillomania neuroimaging studies are lacking. Aims To investigate grey and white matter abnormalities over the whole brain in patients with trichotillomania. Method Eighteen patients with DSM–IV trichotillomania and 19 healthy controls undertook structural magnetic resonance imaging after providing written informed consent. Differences in grey and white matter were investigated using computational morphometry. Results Patients with trichotillomania showed increased grey matter densities in the left striatum, left amygdalo-hippocampal formation, and multiple (including cingulate, supplementary motor, and frontal) cortical regions bilaterally. Conclusions Trichotillomania was associated with structural grey matter changes in neural circuitry implicated in habit learning, cognition and affect regulation. These findings inform animal models of the disorder and highlight key regions of interest for future translational research.

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

Through the combined use of 18F-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.

Relationship of regional brain β-amyloid to gait speed.

Objective: To investigate in vivo the relationship of regional brain β-amyloid (Aβ) to gait speed in a group of elderly individuals at high risk for dementia. Methods: Cross-sectional associations between brain Aβ as measured with [18F]florbetapir PET and gait speed were examined in 128 elderly participants. Subjects ranged from healthy to mildly cognitively impaired enrolled in the control arm of the multidomain intervention in the Multidomain Alzheimer Preventive Trial (MAPT). Nearly all participants presented spontaneous memory complaints. Regional [18F]florbetapir (AV45) standardized uptake volume ratios were obtained via semiautomated quantitative analysis using the cerebellum as reference region. Gait speed was measured by timing participants while they walked 4 meters. Associations were explored with linear regression, correcting for age, sex, education, body mass index (BMI), and APOE genotype. Results: We found a significant association between Aβ in the posterior and anterior putamen, occipital cortex, precuneus, and anterior cingulate and slow gait speed (all corrected p < 0.05). A multivariate model emphasized the locations of the posterior putamen and the precuneus. Aβ burden explained up to 9% of the variance in gait speed, and significantly improved regression models already containing demographic variables, BMI, and APOE status. Conclusions: The present PET study confirms, in vivo, previous postmortem evidence showing an association between Alzheimer disease (AD) pathology and gait speed, and provides additional evidence on potential regional effects of brain Aβ on motor function. More research is needed to elucidate the neural mechanisms underlying these regional associations, which may involve motor and sensorimotor circuits hitherto largely neglected in the pathophysiology of AD.

Neural and Behavioral Endophenotypes in ADHD

In recent years, descriptive symptom-based approaches of attention deficit hyperactivity disorder (ADHD) have been increasingly replaced by more sophisticated endophenotype-based strategies, better suited to investigate its pathophysiological basis, which is inherently heterogeneous. Measurements derived from neuroimaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) constitute endophenotypes of growing interest, capable of providing unprecedented windows on neurochemical and neuroanatomical components of psychiatric conditions. This chapter reviews the current state of knowledge regarding putative neural and behavioral endophenotypes of ADHD, across the lifespan. To this end, recent evidence drawn from molecular and structural neuroimaging studies are discussed in the light of widely accepted neuropsychological and pharmacological models of ADHD.

Quantification of receptor-ligand binding potential in sub-striatal domains using probabilistic and template regions of interest.

Sub-striatal regions of interest (ROIs) are widely used in PET studies to investigate the role of dopamine in the modulation of neural networks implicated in emotion, cognition and motor function. One common approach is that of Mawlawi et al. (2001) and Martinez et al. (2003), where each striatum is divided into five sub-regions. This study focuses on the use of two spatial normalization-based alternatives to manual sub-striatal ROI delineation per subject: manual ROI delineation on a template brain and the production of probabilistic ROIs from a set of subject-specific manually delineated ROIs. Two spatial normalization algorithms were compared: SPM5 unified segmentation and ART. The ability of these methods to quantify sub-striatal regional non-displaceable binding potential (BP(ND)) and BP(ND) % change (following methylphenidate) was tested on 32 subjects (16 controls and 16 ADHD patients) scanned with the dopamine D(2)/D(3) ligand [(18)F]fallypride. Probabilistic ROIs produced by ART provided the best results, with similarity index values against subject-specific manual ROIs of 0.75-0.89 (mean 0.84) compared to 0.70-0.85 (mean 0.79) for template ROIs. Correlations (r) for BP(ND) and BP(ND) % change between subject-specific manual ROIs and these probabilistic ROIs of 0.90-0.98 (mean 0.95) and 0.98-1.00 (mean 0.99) respectively were superior overall to those obtained with template ROIs, although only marginally so for BP(ND) % change. The significance of relationships between BP(ND) measures and both behavioural tasks and methylphenidate plasma levels was preserved with ART combined with both probabilistic and template ROIs. SPM5 virtually matched the performance of ART for BP(ND) % change estimation but was inferior for BP(ND) estimation in caudate sub-regions. ART spatial normalization combined with probabilistic ROIs and to a lesser extent template ROIs provides an efficient and accurate alternative to time-consuming manual sub-striatal ROI delineation per subject, especially when the parameter of interest is BP(ND) % change.

Frailty Index and Cognitive Decline in Alzheimer's Disease: Data from the Impact of Cholinergic Treatment USe Study

To determine whether the Frailty Index (FI) was associated with short‐term cognitive decline (according to changes in Mini Mental State Examination (MMSE) and Alzheimers Disease Assessment Scale–Cognitive subscale (ADAS‐Cog) scores at 1‐year follow‐up) in individuals with Alzheimers disease (AD).