A proof‐of‐principle study of the effect of combined haloperidol and levodopa administration on working memory‐related brain activation in humans

Abstract

Objective: Cognitive deficits including impaired working memory are a hallmark feature of schizophrenia. Dopamine D1 receptor modulated changes in prefrontal cortex function play a potentially important role in the pathology underlying such deficits. However, pharmacological interventions that selectively engage the D1 receptor are severely restricted for research in humans. The present study is a proof-of-principle for enhancing cognitive performance and associated brain activation via indirect D1 stimulation, operationalised by combining the nonselective dopamine agonist L-dopa with the D2-antagonist haloperidol.Methods: Fourteen healthy volunteers received placebo or combined carbidopa (25 mg)/L-dopa (100 mg) plus haloperidol (2 mg) orally on two separate occasions according to a within-subjects crossover design. Drug-induced differences in brain activity were assessed during an N-back working memory task in a 3T magnetic resonance imaging environment. Results:Drug treatment was associated with greater functional connectivity between the dorsolateral prefrontal cortex and areas within the salience network during all N-back trials. Drug treatment was also associated with reduced activation, most prominently in the occipital/temporal brain areas during 2-back performance. Conclusions:This preliminary study provides initial evidence for combined L-dopa/ haloperidol modulation in cognition-related brain areas and networks, which is relevant for the treatment of cognitive impairments in mental illness.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force

“…Nine of 26 studies were classified as good‐quality studies according to the Quality Assessment Tool for Neuroimaging Methodology in Individual Studies criteria 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 (see S3 in supplementary material and individual summary tables, right columns), 14 were categorized as fair‐quality studies, 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 and three studies 50 , 51 , 52 were classified as poor‐quality studies.…”

“…Twenty of the identified studies were conducted in healthy individuals 32 , 33 , 34 , 35 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 with individual group sizes of n = 4–47 and mean age ranges of 20–33 years (see Tables 2 , 3 , 4 ). The methodological quality was “fair” (scores ≥50%) in 13 of these studies, good (scores ≥75%) in four studies and poor (scores<50%) in three studies (Tables 2 , 3 , 4 ).…”

“…Of these, 15 studies used task‐based fMRI with the administration of varied paradigms including n‐back WM tasks, a continuous performance task, a novelty detection task, a variable attentional control task, a psychomotor vigilance task, a delayed‐match‐to‐sample task, a spatial paired associates learning task and a semantic fluency task. 32 , 33 , 34 , 35 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 47 , 48 , 51 , 52 Of the remaining five studies that only involved administration of cognitive tasks outside the scanner, one used ASL with prose recall, n‐back WM, and digit span tasks, 47 one used resting state fMRI with an episodic memory task, 44 one used MRS with an associative learning task, 49 and two used real‐time fMRI with attentional score scale, continuous performance test, digit span, and letter memory tasks. 45 , 46 …”

“…Fourteen studies investigated the effects of pharmacological compounds, 32 , 33 , 34 , 37 , 38 , 39 , 41 , 42 , 47 , 48 , 49 , 50 , 51 , 52 two examined the effects of different cognitive training interventions 35 , 40 and four assessed neuromodulation techniques. 43 , 44 , 45 , 46 …”

The Combination of DAT-SPECT, Structural and Diffusion MRI Predicts Clinical Progression in Parkinson’s Disease

“…Moreover, we employed those imaging measure to predict the future disease progression quantified by the MDS-UPDRS variations between the two time points. As the dopaminergic treatments taken by some patients after the baseline evaluation have substantial effects on the clinical symptoms measured with MDS-UPDRS, we accounted for those effects by applying the prediction models separately to the group of patients receiving medication and to the one without treatment employing off medication clinical assessment (Mueller et al, 2018; van Ruitenbeek et al, 2018).…”