Anales de la RANM

125 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 NEUROTHERAPEUTICS FOR ADHD Katya Rubia An RANM. 2021;138(02): 124 - 131 ADHD: Attention Deficit/Hyperactivity Disorder DLPFC: dorsolateral prefrontal cortex EEG: electroencephalography fMRI: functional magnetic resonance imaging IFC: inferior frontal cortex NIRS: near infrared spectroscopy rIFC: right inferior frontal cortex rTMS: repetitive transcranial magnetic stimulation tDCS: transcranial direct current stimulation TNS: trigeminal nerve stimulation tRNS: transcranial random noise stimulation Attention-Deficit/Hyperactivity Disorder (ADHD) is defined in the DSM-5 as a disorder of persis- ting and impairing symptoms of age-inappropriate inattention, and/or hyperactivity/impulsivity (1). It is one of the most common childhood disorders with a worldwide prevalence of around 7% (2). Problems persist into adulthood in most patients and are associated with comorbidities and poor social and academic outcomes (2). People with ADHD have deficits in higher-level cognitive functions necessary for mature adult goal-directed behaviors, in so-called “executive functions”, that are mediated by late develo- ping fronto-striato-parietal and fronto-cerebe- llar networks (3). The most consistent deficits are in motor response inhibition, working memory, switching, sustained attention and intraindividual response variability (4), as well as timing functions (5, 6). Children are cognitively more impaired than adults with ADHD (4). The gold-standard treatment is with psychostimu- lant medication which enhance catecholamines in the brain, reaching an effect size of ~ 0.8 for parent- ratings of symptoms, with about 70% of patients with ADHD responding to it, followed by second- line treatment with noradrenaline transporter/ receptor blockers Atomoxetine and Guanfacine that also enhance brain catecholamines with effect sizes of 0.56 and 0.67, respectively (7). ADHD medica- tions, however, commonly have side effects and longer-term efficacy has not been demonstrated in meta-analyses, observational or epidemiolo- gical studies (7, 8), possibly due to brain adapta- tion (9). Non-pharmacological treatments are hence preferred by parents and children. Modern neurotherapeutics in the form of neurofee- dback -using functional magnetic resonance imaging (fMRI) or near infrared spectroscopy (NIRS)- or brain stimulation have the advantage that they can target directly the key brain function deficits that have been found in ADHD over the past 2.5 decades of fMRI neuroimaging. These findings of consistent brain structure and function deficits in ADHD has led to ADHD nowadays being considered a neurodevelopmental disorder. Meta- and mega-analyses of structural imaging studies in ADHD have shown reduced grey matter and cortical thickness in frontal, temporal and parietal regions (10-12) as well as reduced grey matter in subcortical regions, most prominently the basal ganglia and insula (10, 12), but also limbic areas such as amygdala and hippocampus (13) (for review see (14)). fMRI studies have provided consistent evidence for dysfunctions in several brain regions, mostly underac- tivations relative to healthy controls, involving lateral inferior and dorsolateral prefrontal cortical regions as well as medial frontal, cingulate and orbital frontal regions, basal ganglia and the dissociated fronto- parietal, fronto-striatal, fronto-limbic and fronto- cerebellar networks they form part of (14). Several fMRI meta-analyses have shown cognitive domain- dissociated underactivations in several frontal, striatal, parietal and cerebellar brain regions in ADHD. We replicated the finding of underactiva- tion in ADHD patients relative to controls in right IFC/insula and striatum in 3 meta-analyses of whole- brain fMRI studies of cognitive control (10, 12, 15). Our meta-analysis of fMRI studies of attention tasks showed reduced activation in ADHD patients relative to healthy controls in right DLPFC, right inferior parietal cortex, caudal basal ganglia and thalamus, which are part of the right hemispheric dorsal attention network (15). Other meta-analyses of attention found additional underactivation in LIST OF ACRONYMS INTRODUC TION de prueba de concepto de la estimulación del nervio trigémino (TNS) mostró efectos de mejora de síntomas clínicos de tamaño mediano, pero requiere una repetición con muestras mayores. En conclusión, las neuroterapias son atractivas debido a sus efectos secundarios mínimos y efectos potenciales a largo plazo sobre la plasticidad cerebral que los medicamentos no pueden ofrecer; sin embargo, están aún en pañales. Requieren comprobaciones sistemáticas de protocolos óptimos en muestras grandes, incluyendo lugares óptimos para la estimulación/neurofeedback, frecuencia óptima de las sesiones de tratamiento, o amplitud óptima de la estimulación. Es importante recalcar que necesitarán mostrar su potencial en tratamientos individualizados, aportando una comprensión de la predicción de la respuesta individual al tratamiento. FUNC TIONAL NEUROIMAGING MARKERS OF ADHD