2021

1. Right prefrontal activation predicts ADHD and its severity: A TMS-EEG study in young adults

   Itay Hadas, Aviad Hadar, Avi Lazarovits, and 2 more authors

   Progress in Neuro-Psychopharmacology and Biological Psychiatry, Dec 2021

   Abs DOI

   Objective Here we bring a neurophysiological diagnostic tool, based on pathophysiologically-relevant brain region, that is critical for reducing the variability between clinicians, and necessary for quantitative measures of ADHD severity. Methods 54 healthy and 57 ADHD adults participated in the study. Electroencephalography (EEG) was recorded when combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex and also recorded during the Stop Signal task. Results TMS evoked potentials (TEPs) and the event related potential (ERP) components in the Stop Signal task were found to be significantly reduced in ADHD relative to the matched healthy controls. Stop signal reaction time (SSRT) and stopping accuracy was found to correlate with the ERP signal, and ADHD severity correlated with the TEP signal. Cortical activity (early TEP and Stop Signal ERP) diagnostic model yielded accuracy of 72%. Conclusion TEPs and ERPs reveal that right PFC excitability was associated with ADHD severity, and with behavioral impulsivity – as a hallmark of ADHD pathology. This electrophysiological biomarker supports the potential of objective diagnosis for ADHD. Significance Such tools would allow better assessment of treatment efficacy and prognosis, may advance understanding of the pathophysiology of the disease and better the public’s attitudes and stigma towards ADHD. Trial Registration: Trial to Evaluate the Efficacy of the HLPFC Coil Deep Transcranial Magnetic Stimulation System in Treating Attention Deficit and Hyperactivity Disorder (ADHD) in Adults, https://clinicaltrials.gov/ct2/show/NCT01737476, ClinicalTrials.gov number NCT01737476

2017

1. Answering the missed call: Initial exploration of cognitive and electrophysiological changes associated with smartphone use and abuse

   Aviad Hadar, Itay Hadas, Avi Lazarovits, and 3 more authors

   PLOS ONE, Jul 2017

   Number: 7

   Abs DOI

   Background Smartphone usage is now integral to human behavior. Recent studies associate extensive usage with a range of debilitating effects. We sought to determine whether excessive usage is accompanied by measurable neural, cognitive and behavioral changes. Method Subjects lacking previous experience with smartphones (n = 35) were compared to a matched group of heavy smartphone users (n = 16) on numerous behavioral and electrophysiological measures recorded using electroencephalogram (EEG) combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex (rPFC). In a second longitudinal intervention, a randomly selected sample of the original non-users received smartphones for 3 months while the others served as controls. All measurements were repeated following this intervention. Results Heavy users showed increased impulsivity, hyperactivity and negative social concern. We also found reduced early TMS evoked potentials in the rPFC of this group, which correlated with severity of self-reported inattention problems. Heavy users also obtained lower accuracy rates than nonusers in a numerical processing. Critically, the second part of the experiment revealed that both the numerical processing and social cognition domains are causally linked to smartphone usage. Conclusion Heavy usage was found to be associated with impaired attention, reduced numerical processing capacity, changes in social cognition, and reduced right prefrontal cortex (rPFC) excitability. Memory impairments were not detected. Novel usage over short period induced a significant reduction in numerical processing capacity and changes in social cognition.

2016

1. Exposure to salient, dynamic sensory stimuli during development increases distractibility in adulthood

   Itay Hadas, Ram Gal, Lihi Bokovza, and 3 more authors

   Scientific Reports, Feb 2016

   Abs DOI

   It has been suggested that excessive exposure of children to the dynamic and highly salient audio-visual stimuli conveyed by electronic media may induce attention-related deficits in adulthood.

2. Long-lasting attentional impairments induced by sensory loading

   Itay Hadas

   Feb 2016

   Abs

   Executive functions are considered to be mostly heritable psychological traits (Engelhardt et al., 2015; Friedman et al., 2008). Throughout the lifespan, executive functions can be acutely affected by distracting environmental settings, but evidence that correlates non-aversive, chronic, and exogenic stimuli to long-term effects on these functions is scarce. Such observations are of great importance because the modern environment surrounds us with pervasive and salient stimuli in the form of electronic media (e.g., television, smartphones, etc.), which can continuously grab or distract our attention. As such, this phenomenon requires new experimental approaches that will enable researchers to determine a causal link between electronic media exposure and impairments of executive functions. The aim of this thesis is to actualize that by establishing a novel animal model and to manipulate human volunteers in the attempt to draw a causal link between attentional modifications and chronic exposure to attention-grabbing stimuli. Animal arm: Most of the scientific work involving animal models for attentional impairments explores the neurophysiological mechanisms underlying attention. Those studies usually employ an invasive physiological, genetic, or pharmacological manipulation, which are means that do not accurately model the etiology of human attentional impairments. As such, a novel animal model that adequately models human attention-related deficits and disorders is needed. To that end, I developed an animal model where long-lasting attentional impairments were induced by applying excessive olfactory stimulation (“sensory loading”) to young rats. The stimuli used were non-aversive, dynamic, salient, and ecologically relevant, especially in the context of the digital media in the modern environment (taking into account that rats rely mostly on olfaction, like humans rely on vision). The model was developed based on studies in which children exposed to “fast- paced” electronic media at young ages demonstrated attentional deficits later in life. By using this novel animal model in a tightly controlled set-up, I found that rats exposed to developmental, dynamic, and salient stimulation (DDSS) demonstrated altered behavior in a 5-choice serial reaction time task (5-CSRTT) apparatus. Initially, I found that the DDSS group demonstrated higher approaching behavior toward the reward chamber. Thereafter, during training, the performances of the DDSS group was better than that of the control group; but this effect was reversed during the distractibility tests, in which the DDSS group demonstrated reduced and more variable performance. At the anatomical-molecular level, I found that brain-derived neurotrophic factor (BDNF) levels in the dorsal striatum of the DDSS rats were significantly higher than that of the control rats. BDNF is a necessary signaling protein in many cognitive functions and is considered to be a reliable proxy for many forms of neuronal plasticity. The animal data provide empirical evidence that a continuous exposure to dynamic, salient stimuli has a long-term influence over attentional functions in adulthood and that this effect may be mediated by neurochemical alterations in the dorsal striatum. Taken together, the animal findings suggest an altered attribution of incentive saliency, a cognitive mechanism that is believed to be tightly related to ADHD symptomology. In continuation of my animal work, I looked further for how chronic, dynamic, and salient exogenous stimuli can affect human cognitive functions similarly to what has been found in rats. Human arm: Using a translational approach, I explored the effect of a highly stimulating environment on human attentional behavior. In that regard, converging evidence suggests the immense attention-grabbing capacity of smartphone devices, one that is equivalent to that of the highly stimulating odor environment in rats. Users always have their smartphones with them throughout the day, which serves as an example of the pervasiveness of electronic media in contemporary human lives. In the first correlative phase of the study, 16 “heavy” smartphone users were recruited out of 2711 who responded to an online questionnaire. Following enrollment into the study, these heavy users were compared to a group of 35 non-users (i.e., individuals who owned a regular phone and had never owned a smartphone) in a battery of tests that were used for the assessment of ADHD symptomology and pathophysiology. These tests included the gold standard questionnaire for assessment of ADHD (the CAARS), an EEG recording during a stop-signal task that assessed inhibitory control (one of the ADHD hallmarks), and an information processing capacity task, which is known to be aberrant in ADHD patients. In the second manipulative phase, the non-users were divided into two groups: one group continued to use their own phones (n=7), but the other group received smartphones (n=8). Following a six month period of exposure, the two groups were re-examined using the same battery of tests. As such, the first phase of the study was correlational in nature and was designed to assess the possible impact of heavy smartphone use; the second phase was manipulative in nature and was designed to allow a better deduction of causality between behavioral impairments and smartphone use. In the first phase of the study, I found differences between heavy-users and non-users in terms of inattentiveness, impulsiveness, and ADHD-like symptoms, as measured by CAARS. In addition, heavy users demonstrated reduced arithmetic processing abilities compared to non-users. In the manipulative phase of the study, I found that, compared to controls, exposure to smartphones led to a development of inattentiveness, to higher intra-individual reaction-time variability in the stop-signal task, and to modified brain activity that resembled ADHD psychopathology. These findings demonstrate a causal relationship between smartphone use, affected executive functioning, and ADHD-like symptomology. Faulty response inhibition as measured in the stop-signal task is considered to be an endophenotype of ADHD and also believed to stem from maladaptive “over” approaching tendencies to environmental stimuli. Thus, these findings may imply that the manipulated group changed their approaching behavior tendencies (i.e., changed the way in which they attribute incentive saliency). Taken together, the animal and the human studies demonstrated a causal link between chronic exposure to dynamic and attention-grabbing stimuli and changes in executive functioning. As such, these findings support the notion that heightened exposure to electronic media in contemporary human society is related to the increasing occurrence of attention-related disorders.