Synaptic gating and ADHD: A biological theory of comorbidity of ADHD and anxiety

School of Psychiatry, University of New South Wales, Prince of Wales Hospital, Randwick, Australia.
Neuropsychopharmacology (Impact Factor: 7.05). 10/2004; 29(9):1589-96. DOI: 10.1038/sj.npp.1300469
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ABSTRACT To derive a biologically based theory of comorbidity in Attention Deficit Hyperactivity Disorder (ADHD). Theoretical concepts and empirical studies were reviewed to determine whether the behavioral inhibition concept provided an understanding of biological processes involved in comorbidity in ADHD. Empirical studies of ADHD have shown comorbidity of ADHD and anxiety, while studies of behavioral inhibition tend to suggest independent disruptive and anxiety traits. This paradox can be resolved by an understanding of the dynamics of mesolimbic dopamine (DA) systems, where reward and delay of reinforcement are determined by tonic/phasic DA relationships, resulting in impulsive 'fearless' responses when impaired. On the other hand, comorbid anxiety is related to impaired synaptic processes, which selectively gate fear (or aggressive) responses from the amygdala at the accumbens. Monosynaptic convergence between prefrontal, hippocampal, and amygdala projection neurons at the accumbens allows the operation of a synaptic gating mechanism between prefrontal cortex (PFC), hippocampus, and amygdala. Impairment of this mechanism by lowered PFC inhibition allows greater amygdala input, and anxiety-related processes more impact, over the accumbens. In conclusion, a dual theory incorporating long-term tonic/phasic mesolimbic DA relationships and secondly impairment of PFC and hippocampal inputs to synaptic gating of anxiety at the accumbens has implications for comorbidity in ADHD, as well as for possible pharmacological interventions, utilizing either stimulant or axiolytic interventions. The use of DA partial agonists may also be of interest.

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Available from: Florence Levy, Feb 24, 2014
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    • "Prefrontal and limbic systems - in particular, the amygdala - have important roles in the pathophysiology of ADHD.5,6,9,10,11,12) Children with ADHD showed an alteration of amygdala function compared to healthy controls, along with more hyperactivity and inattention, fear learning, negative emotions, and negative perceptions of emotional stimuli.13,14,15) Other studies found that emotional lability and impulsive behavior in children correlated with dysfunction in the amygdala.16,17) "
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    ABSTRACT: Objective Recent pediatric studies have suggested a correlation between decreased amygdala volume and attention deficit and hyperactivity disorder (ADHD) symptoms, including the emotional dysregulation. To investigate the hypothesis that medication treatment of ADHD specifically improves amygdala function, we used 1H magnetic resonance spectroscopy (MRS) to study the effect of 12 weeks of treatment with daily 20 mg long-acting methylphenidate on the Glu/Cr, NAA/Cr, Cho/Cr, and mI/Cr ratios in the amygdala of medication-naïve children with ADHD. Methods This was a prospective study, using a pre- and post-test design, on a single group of 21 children (average age 8.52 years, 17 males and 4 females) diagnosed with ADHD. Low Time Echo MRS scans sampled voxels of interest (1.5×1.5×2.0) from both the right and left amygdala. Results There was significant clinical improvement after 12 weeks of treatment with 20 mg long-acting methylphenidate. On 1H MRS, there were no statistical significant differences of NAA/Cr ratio, Cho/Cr ratio, mI/Cr ratio before and after 12 weeks administration of 20 mg long-acting methylphenidate both in the right and left amygdala. In addition, Glu/Cr ratio decreased 14.1% in the right amygdala (p=0.029) and 11.4% in the left amygdala (p=0.008). Standardized mean effect sizes ranged from 0.14-0.32. Conclusion The findings are consistent with the possibility that hyperglutamatergic processes in the amygdale are related to the hyperactive-impulsive symptoms of ADHD.
    Clinical Psychopharmacology and Neuroscience 08/2014; 12(2):137-41. DOI:10.9758/cpn.2014.12.2.137
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    • "Clinically, the concept of input-selectivity can be extended to (selective) attention and working-memory, as well as disease states such as ADHD (Levy, 2004), anxiety, and schizophrenia (Grace, 2000); which are indeed already indications explored for tDCS (Kang et al., 2009; Faber et al., 2012; Demirtas-Tatlidede et al., 2013; Shiozawa et al., 2013). The prefrontal cortex, an anatomical target for several indications including depression (Loo et al., 2012), is indeed implicated in executive function and differentiating among (conflicting) inputs. "
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    ABSTRACT: Transcranial Direct Current Stimulation (tDCS) is investigated for a broad range of neuropsychiatric indications, various rehabilitation applications, and to modulate cognitive performance in diverse tasks. Specificity of tDCS refers broadly to the ability of tDCS to produce precise, as opposed to diffuse, changes in brain function. Practically, specificity of tDCS implies application-specific customization of protocols to maximize desired outcomes and minimize undesired effects. Especially given the simplicity of tDCS and the complexity of brain function, understanding the mechanisms leading to specificity is fundamental to the rational advancement of tDCS. We define the origins of specificity based on anatomical and functional factors. Anatomical specificity derives from guiding current to targeted brain structures. Functional specificity may derive from either activity-selectivity, where active neuronal networks are preferentially modulated by tDCS, or input-selectivity, where bias is applied to different synaptic inputs. Rational advancement of tDCS may require leveraging all forms of specificity.
    Frontiers in Human Neuroscience 10/2013; 7:688. DOI:10.3389/fnhum.2013.00688 · 2.99 Impact Factor
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    • "Imaging studies in ADHD revealed not only alterations in the structure and function of the prefrontal cortex, but also in the amygdala and the hippocampus [5]–[8] which are both critically involved in emotional processes [9]–[11]. In particular, the affected interplay between these regions is assumed to cause emotional problems in ADHD during daytime [12]. Moreover, ADHD is associated with sleep disorders [13], [14], and has to be seen as a “24h syndrome” which also affects sleep and its functions [15], [16]. "
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    ABSTRACT: Fronto-limbic brain activity during sleep is believed to support the consolidation of emotional memories in healthy adults. Attention deficit-hyperactivity disorder (ADHD) is accompanied by emotional deficits coincidently caused by dysfunctional interplay of fronto-limbic circuits. This study aimed to examine the role of sleep in the consolidation of emotional memory in ADHD in the context of healthy development. 16 children with ADHD, 16 healthy children, and 20 healthy adults participated in this study. Participants completed an emotional picture recognition paradigm in sleep and wake control conditions. Each condition had an immediate (baseline) and delayed (target) retrieval session. The emotional memory bias was baseline-corrected, and groups were compared in terms of sleep-dependent memory consolidation (sleep vs. wake). We observed an increased sleep-dependent emotional memory bias in healthy children compared to children with ADHD and healthy adults. Frontal oscillatory EEG activity (slow oscillations, theta) during sleep correlated negatively with emotional memory performance in children with ADHD. When combining data of healthy children and adults, correlation coefficients were positive and differed from those in children with ADHD. Since children displayed a higher frontal EEG activity than adults these data indicate a decline in sleep-related consolidation of emotional memory in healthy development. In addition, it is suggested that deficits in sleep-related selection between emotional and non-emotional memories in ADHD exacerbate emotional problems during daytime as they are often reported in ADHD.
    PLoS ONE 05/2013; 8(5):e65098. DOI:10.1371/journal.pone.0065098 · 3.23 Impact Factor
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