Genetic modulation of functional brain activity of attention-deficit/hyperactivity disorder-related working memory process
Final Report Abstract
The aim of the Junior Research Group “Genetic Imaging” was to investigate the functional neuroanatomy of attention, impulsivity, and emotion processing (using different brain-imaging techniques like functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS) and electroencephalography (EEG) relevant for ADHD. In addition, the influence of genetic variation on functional neuroanatomy and brain activity was to be evaluated. In a first step we investigated ADHD-relevant functions in healthy controls to elaborate suitable experimental designs (to asses these functions) and tested for a genetic modulation of the corresponding brain functions. We found that life stress differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features during emotional processing. Measuring the event-related EEG potentials additionally revealed that both the 5-HTT and TPH2 gene variations as well as the COMT val158met genotype modulate the neural correlates of emotional processing. In a further study we found that executive functions and the corresponding prefrontal brain activity are also modulated by genetic variations, for example by the DTNBP1 gene during response inhibition in an event-related potential study and by the DRD4 gene variation during working memory processes measured by near-infrared spectroscopy. In summary we confirmed in different studies the influence of genetic variations on functional neuroanatomy relevant for ADHD. In the second step we compared adult ADHD patients and healthy controls with regard to emotional processing and executive functions. In a first fMRI study we investigated regional activation changes and functional connectivity differences during working memory processes in healthy controls and adult ADHD patients. We found during the delay period of the activation task that ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. Using again an event-related potential approach, we could show that ADHD patients have attenuated error-related negativity and positivity potentials, indicating a deficient action monitoring system. Besides these executive function deficits in ADHD patients, theoretical models argue that emotional deficits add important aspects to understand the clinical symptoms of ADHD. In one of our studies we therefore presented emotional pictures (positive, negative and neutral) and measured the event-related potentials in 32 adults with ADHD (mostly of the combined subtype) and 32 healthy controls. We calculated the early posterior negativity (EPN), which is characterized by more negative values for emotional compared to neutral stimuli. The results showed significantly reduced EPN values to positive stimuli for the ADHD patients compared to healthy controls. In the negative stimuli condition, we did not find any significant differences between the two groups. In a second fMRI study we showed that the brain activity of the reward system (especially the ventral striatum) is negatively correlated with ADHD symptoms in a student population. Both studies thus confirmed that ADHD related symptoms are associated with less reactivity to positive visual stimuli, which might be interpreted as a sign of a dysfunctional motivationalreward system in adult ADHD patients.
Publications
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(2007) Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb Cortex 17(5): 1160-1163
Herrmann M J, Huter T, Muller F, Muhlberger A, Pauli P, Reif A, Renner T. Canli T, Fallgatter A J, Lesch KP
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(2007) D4 receptor gene variation modulates activation of prefrontal cortex during working memory. Eur J Neurosci, 26(10): 2713-2718
Herrmann MJ, Walter A, Schreppel T, Ehlis AC, Pauli P, Lesch KP, Fallgatter AJ
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(2009) Catechol-O-methyltransferase val158met genotype affects neural correlates of aversive stimuli processing. Cognitive, Affective, and Behavioral Neurociences 159: 1032-1043
Herrmann MJ, Würflein H, Schreppel T, Koehler S, Mühlberger A, Reif A, Canli T, Romanos M, Jacob C P, Lesch KP. and Fallgatter AJ
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(2009) Emotional deficits in adult ADHD patients: an ERP study. Social Cognitive and Affective Neuroscience 4: 340-345
Herrmann MJ, Schreppel T, Biehl SC, Jacob C, Heine M, Boreatti-Hümmer A, Mühlberger A., Fallgatter AJ
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(2010) Neural correlates of performance monitoring in adult patients with Attention Deficit Hyperactivity Disorder (ADHD). World Journal of Biological Psychiatry 11: 457-64
Herrmann MJ, Pfahler K, Huter T, Jacob C, Heine,M, Boreatti-Hümmer A, Ehlis AC, Scheuerpflug P, Lesch KP, Fallgatter AJ
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(2011) ADHD related behaviors are associated with brain activation in the reward system. Neuropsychologia. 49: 426-434
Stark R, Bauer E, Merz CJ, Zimmermann M, Reuter M, Plichta MM, Kirsch P., Lesch KP, Fallgatter AJ, Vaitl D, Herrmann MJ
