Charlotte R. Housden

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease

Impulsivity is common in Parkinson’s disease. In a double-blind, placebo-controlled study with multi-modal imaging, Ye et al. reveal improved response inhibition in some patients receiving the SSRI citalopram, including those with advanced disease. Improvements correlated with preserved frontostriatal structural connectivity and drug-induced prefrontal activity, highlighting the need for patient stratification in trials.

Targeting impulsivity in Parkinson’s disease using atomoxetine

In a double-blind randomized placebo-controlled study, Kehagia et al. investigate the effects of a single dose of atomoxetine, a selective noradrenaline reuptake inhibitor, in 25 patients with Parkinson’s disease. Consistent with the presence of a longstanding noradrenergic deficit, atomoxetine improved stopping accuracy, and reduced reflection impulsivity during decision making.

Effect of Pharmacological Enhancement on the Cognitive and Clinical Psychomotor Performance of Sleep-Deprived Doctors: A Randomized Controlled Trial

Objectives: To investigate the effect of modafinil 200 mg on the performance of a cohort of healthy male doctors after 1 night of supervised sleep deprivation. Summary Background Data: Sleep-deprived and fatigued doctors pose a safety risk to themselves and their patients. Yet, because of the around-the-clock nature of medical practice, doctors frequently care for patients after periods of extended wakefulness or during circadian troughs. Studies suggest that a group of substances may be capable of safely and effectively reversing the effects of fatigue. However, little work has been done to investigate their role within our profession. Methods: We conducted a parallel, double-blind, randomized, and placebo-controlled study to investigate the effect of pharmacological enhancement on performance doctors. Thirty-nine healthy male resident doctors received either lactose placebo (n = 19) or modafinil 200 mg (n = 20) after 1 night of sleep deprivation. A selection of CANTAB neuropsychological tests was used to assess higher cognitive function. Clinical psychomotor performance was assessed using the Minimally Invasive Surgical Trainer Virtual Reality. Assessments were carried out between 6.00 AM and approximately 8.00 AM. Results: Modafinil improved performance on tests of higher cognitive function; participants in the modafinil group worked more efficiently when solving working memory (F 1,38 = 5.24, P = 0.028) and planning (F 1,38 = 4.34, P = 0.04) problems, were less-impulsive decision makers (F 1,37 = 6.76, P = 0.01), and were more able to flexibly redirect their attention (F 1,38 = 4.64, P = 0.038). In contrast, no improvement was seen in tests of clinical psychomotor performance. Conclusions: Our results suggest that fatigued doctors might benefit from pharmacological enhancement in situations that require efficient information processing, flexible thinking, and decision making under time pressure. However, no improvement is likely to be seen in the performance of basic procedural tasks.

Improving Response Inhibition in Parkinson's Disease with Atomoxetine

Background Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinsons disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinsons disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinsons disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinsons disease, the individual patients response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016.

Pharmacological enhancement of performance in doctors.

The benefits have not been proved, and more evidence is needed

Apathy, ventriculomegaly and neurocognitive improvement following shunt surgery in normal pressure hydrocephalus

Introduction. Apathy – impaired motivation and goal-directed behaviour – is a common yet often overlooked symptom in normal pressure hydrocephalus (NPH). Caudate atrophy often yields apathetic symptoms; however, this structural and functional relationship has not yet been explored in NPH. Additionally, little is known about the relationship between apathy and post-shunt cognitive recovery. Methods. This audit investigated whether apathetic symptoms improve following shunt surgery in NPH, and whether this relates to cognitive response. In addition, we assessed the relationship between ventriculomegaly and apathy using the bicaudate ratio. Twenty-two patients with NPH completed the Mini-Mental State Examination (MMSE), the Apathy Evaluation Scale (AES) and the Geriatric Depression Scale (GDS) before and 3–9 months after shunt surgery. Pre-operative ventriculomegaly was correlated with pre-operative AES and GDS scores. Difference scores (post-shunt minus baseline values) for AES and GDS were correlated with cognitive outcome. Results. Greater pre-operative ventriculomegaly was associated with increased level of apathy and depression. A reduction in apathetic symptoms following shunt surgery was associated with improved performance on the MMSE. Conclusions. Apathy may be indicative of a greater degree of subcortical atrophy in NPH and may relate to functional outcome.

CHANGES TO VALIDITY OF ONLINE COGNITIVE ASSESSMENT IN YOUNG AND OLDER ADULTS: A COMPARISON TO SUPERVISED TESTING USING THE CANTAB BATTERY

O3-03-03 CHANGES TO VALIDITY OF ONLINE COGNITIVE ASSESSMENT IN YOUNG AND OLDER ADULTS: A COMPARISON TO SUPERVISED TESTING USING THE CANTAB BATTERY Francesca K. Cormack, Nick Taptiklis, Rosemary A. Abbott, Melis Anat€urk, Ian Cartland, Lotte Coppieters, Charlotte Housden, Jennifer H. Barnett, Cambridge Cognition, Cambridge, United Kingdom; Table 3 Relationships between biomarkers and CogState variables. Ab1⁄4amyloid-beta. Ttau1⁄4total tau. PiB1⁄4Pittsburgh compound B. CPAL1⁄4continuous paired associates learning task; GMCT1⁄4Groton maze chase test; GML1⁄4Groton maze learning; GMR1⁄4Groton maze recall; OCL1⁄4one card learning test; ONB1⁄4one-back; TWOB1⁄4two-back. Acc1⁄4arcsine proportioncorrected accuracy, higher score is better; MPS1⁄4moves per second, higher score is better; err1⁄4errors, high score is worse. P-value is for the coefficient of the biomarker variable in a multiple regression controlling for age, sex, literacy, and computer familiarity.

Neurocognitive testing in the emergency department: A potential assessment tool for mild traumatic brain injury

Despite mild traumatic brain injury (mTBI) accounting for 80% of head injury diagnoses, recognition of individuals at risk of cognitive dysfunction remains a challenge in the acute setting. The objective of this study was to evaluate the feasibility and potential role for computerised cognitive testing as part of a complete ED head injury assessment.

Advanced magnetic resonance imaging and neuropsychological assessment for detecting brain injury in a prospective cohort of university amateur boxers

Background/aim The safety of amateur and professional boxing is a contentious issue. We hypothesised that advanced magnetic resonance imaging and neuropsychological testing could provide evidence of acute and early brain injury in amateur boxers. Methods We recruited 30 participants from a university amateur boxing club in a prospective cohort study. Magnetic resonance imaging (MRI) and neuropsychological testing was performed at three time points: prior to starting training; within 48 h following a first major competition to detect acute brain injury; and one year follow-up. A single MRI acquisition was made from control participants. Imaging analysis included cortical thickness measurements with Advanced Normalization Tools (ANTS) and FreeSurfer, voxel based morphometry (VBM), and Tract Based Spatial Statistics (TBSS). A computerized battery of neuropsychological tests was performed assessing attention, learning, memory and impulsivity. Results During the study period, one boxer developed seizures controlled with medication while another developed a chronic subdural hematoma requiring neurosurgical drainage. A total of 10 boxers contributed data at to the longitudinal assessment protocol. Reasons for withdrawal were: logistics (10), stopping boxing (7), withdrawal of consent (2), and development of a chronic subdural hematoma (1). No significant changes were detected using VBM, TBSS, cortical thickness measured with FreeSurfer or ANTS, either cross-sectionally at baseline, or longitudinally. Neuropsychological assessment of boxers found attention/concentration improved over time while planning and problem solving ability latency decreased after a bout but recovered after one year. Conclusion While this neuroimaging and neuropsychological assessment protocol could not detect any evidence of brain injury, one boxer developed seizures and another developed a chronic sub-dural haematoma.