A proposed model to explain the effects of stimulants in
ADHD includes the inhibitory influences of frontal cortical
activity, predominantly noradrenergic, acting on lower
(striatal) structures that are related to direct DA agonists.7
Contemporary support of this notion includes preclinical
work by Arnsten and Li.32 demonstrating important effects
of stimulants on prefrontal cortex (PFC).
    Work indicates that the stimulants affect not only
    DA but also NE.16,31 For instance, Markowitz et al.31 re-
    cently reported high levels of in vitro binding of MPH
    at the NE transporter that was, interestingly, preferential
    for the d- versus l-isomer. Yet, whereas the striatum is
    rich in DA transporter, a paucity of NE transporters exist
    in the striatum proper.32 In contrast, the PFC, a brain
    region consistently implicated in ADHD, is rich in NE.32
    α2A-Adrenoceptors are located both presynaptically and
    postsynaptically on NE neurons. As recently reviewed by
    Arnsten and Li,32 DA works mainly via the D1 receptor,
    which is rich in the PFC (and is stimulated by the stimu-
    lants). Less is known about the distribution and role of the
    D2–D4 receptors in the PFC, although the D4 receptor also
    has affinity for NE. Rat models suggest that MPH at “lower
    therapeutic doses” stimulates NE α2A, resulting in im-
    proved frontal lobe functioning.33

[7] Zametkin A, Liotta W. The neurobiology of attention-deficit/hyperactivity disorder. J Clin Psychiatry 1998;59(suppl 7):17-23

[16] Kuczenski R. Biochemical actions of amphetamine and other stimulants. In: Creese I, ed. Stimulants: Neurochemical, Behavioral, and Clinical Perspectives. New York, NY: Raven Press, 1983

[31] Markowitz JS, DeVane CL, Pestreich L, et al. Session 1-87-differentiation of d-,L- and dl-methylphenidate through in vitro pharmacological screening. In: Abstracts: Oral and Poster Presentations of the NCDEU 45th Annual Meeting; June 6-9, 2005; Boca Raton, Fla. I-87:186

[32] Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 2005;57:1377-1384

[33] Arnsten AF, Dudley AG. Methlyphenidate improves prefrontal cortical cognitive function through alpha2 adrenocepter and dopamine D1 receptor actions: relevance to therapeutic effects in attention deficit hyperactivity disorder. Behav Brain Funct 2005;1:2


biomodel - inference of neurophysiological mechanisms via quantitative modelling

corticothalamic hypoarousal in ADHD see: Barry et al., 2003 Defrance et al., 1996 Satterfield and Cantwell, 1974

"In summary, stimulant medications could well act to suppress the activity of the TRN, thereby increasing thalamocortical and synaptic activity."

TRN = thalamic reticular nucleus

locus coeruleus

individuals with ADHD that respond to Dexedrine or Ritalin tend to have an abnormally high level of delta-theta EEG power, low skin conductance. Suggests a condition of cortical hypoarousal.

(are delta-theta EEG waves indicative of boredom?)

increased activity involving inhibitory neurons, such as those in the thalamic reticular nucleus (TRN)

see Row et al, 2004a,c

"Other researchers (McCormick, 1989; Sherman and Guillery, 2001; Steriade et al., 1991) and recent work using the same biophysical model of the cortex (Robinson et al, 2001b, 2004; Rowe et al, 2004b) have shown that increased inhibitory activity from the TRN in particular is directly involved in the generation of delta-theta activity during reduced states of arousal.

abnormal increase in the activity of short range inhibitory and excitatory stellate cells and neurons in the TRN (Rowe et al, 2004a)

In another prior study, activity in the intrathalamic network involving the TRN was also found to be positively correlated with increases in delta-theta EEG power (Rowe et al, 2004b) consistent with the delta-theta abnormalities in ADHD.

intrathalamic network activity due to tonic over-stimulation of the TRN by the locus coeruleus (LC) NA projections

LC neurons can increase TRN activity (see Destexhe et al, 1994; McCormick, 1989; Sherman and Guillery, 2001), and other work suggesting a LC overdrive in ADHD)

proposed antagonistic effects of stimulant medication upon LC activity

Konrad et al., 2003; Pliszka et al, 1996; Solanto, 1998

Stimulant medications are known to reduce the activity of the LC:

  • Pliszka et al., 1996
  • Solanto, 1998

LC is known to stimulate the TRN

  • Destexhe et al, 1994
  • McCormick, 1989
  • Sherman and Guillery, 2001

locus coeruleus

indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.

The Role of Locus Coeruleus in the Regulation of Cognitive Performance


Noradrenergic locus coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.

waking state gene expression

l Gene Expression in the Waking State: A Role for the Locus Coeruleus

Chiara Cirelli, Maria Pompeiano, Giulio Tononi

Several transcription factors are expressed at higher levels in the waking than in the sleeping brain. In experiments with rats, the locus coeruleus, a noradrenergic nucleus with diffuse projections, was found to regulate such expression. In brain regions depleted of noradrenergic innervation, amounts of c-Fos and nerve growth factor-induced A after waking were as low as after sleep. Phosphorylation of cyclic adenosine monophosphate response element-binding protein was also reduced. In contrast, electroencephalographic activity was unchanged. The reduced activity of locus coeruleus neurons may explain why the induction of certain transcription factors, with potential effects on plasticity and learning, does not occur during sleep.

Prefrontal projections to thalamic reticulur nucleus

Prefrontal projections to the thalamic reticular nucleus form a unique circuit for attentional mechanisms


Society for Neuroscience

The unique prefrontal– TRN interactions combined with the pacemaker attributes of TRN in the sleep–wake cycle are consistent with the hypothesis that TRN acts as the attentional searchlight of the brain (Crick, 1984).

In the rat visual system, for example, a focus of attention is transmitted from the visual cortex to the thalamus, generating a core of excitation surrounded by inhibition initiated by the di- synaptic cortico-reticulo-geniculate pathway (Montero, 1999). Approximately half of TRN synapses on anterior and mediodor- sal thalamic nuclei in monkeys are with GABAergic neurons, suggesting disinhibition of thalamic relay neurons projecting to prefrontal cortices (Kultas-Ilinsky et al., 1995; Tai et al., 1995). Consistent with this circuit, lesions of TRN increase the incidence of inhibition of thalamocortical projection neurons by local GABAergic neurons (Pinault, 2004; Fuentealba and Steriade, 2005).

The widespread terminations of prefrontal areas 46 and 13 in TRN may help modulate signals conveyed by efferents from tem- poral sensory association cortices in the same TRN sites. Efferents from area 46 overlap in TRN with projections from inferior tem- poral cortices associated with visual perception and visual mem- ory (Fuster et al., 1981; Gross, 1994). Area 46 processes detailed sensory information, has a key role in working memory (Goldman-Rakic, 1996; Fuster, 1997; Funahashi and Takeda, 2002), and is connected with premotor cortices for action (Matelli et al., 1986; Barbas and Pandya, 1987). Conversely, area 13 has robust connections with limbic structures and is associated with emotional processing (Barbas, 2000). The interface of pre- frontal–sensory association pathways in TRN could have a role in selecting relevant and motivationally significant signals and sup- pressing distractors. The widespread prefrontoreticular projec- tions may thus contribute to the supervisory and modulatory effects that specific prefrontal areas exert over other cortices.

from another Rowe paper:

During increased arousal, the tonic firing activity of LC neurons increases (Rasmussen et al., 1986; Reiner, 1986). Many studies have found that these neurons can also increase the firing rate of inhibitory neurons in the TRN (Destexhe & Sejnowski, 2002; Sherman & Guillery, 2001), thereby indirectly exerting inhibitory effects on TC relay neurons. Overactivity of the LC in ADHD may therefore lead to over-stimulation of the TRN, potentially pushing these individuals closer to a state of cortical activity that is characteristic of high inhibitory TRN activity, leading to reduced cortical arousal and increased delta–theta activity. This process would also interfere with the relay of internal and external neural information via the TC relay neurons. Rapid information transfer requires rapid tonic firing of TC relay neurons, which closely follows incoming stimuli (Fanselow et al., 2001; Sherman, 2001). However, a tonic increase in TRN activity is likely to interfere with this relay process, due to an over-inhibition of the relay neurons. -- so no information is getting throug hthe TC relay neurons due to high inhibitory TRN activity?

cortical hypoarousal - abnormally high level of delta-theta EEG power - increased inhibitory activity from the TRN causes the same EEG readings

stimulants are known to reduce the activity of LC

TRN overstimulated by LC in ADHD

ADHD: increased inhibitory activity of TRN

ADHD: a condition cortical hypoarousal

- hypoarousal due to increased inhibitory activity of TRN
- does TRN overstimulation lead to inhibition of thalamocortical projection neurons? (i.e., almost the same as if the TRN was lesioned)

ADHD: abnormal increase in the activity of short range inhibitory and excitatory stellate cells and neurons in the TRN (Rowe et al, 2004a)

prefrontal projections (i.e. layer 5 and 6) to TRN can regulate the activity of thalamic relay neurons in MD, VA, and AM.

disinhibition (i.e., not excitatory but not inhibitory either) of thalamic relay neurons projecting to prefrontal cortices; disinhibition is caused by TRN synapses on anterior and mediodorsal thalamic nuclei (study was done on monkeys)

lesions of TRN increase the incidence of inhibition of thalamocortical projection neurons by local GABAergic neurons

TRN's GABA-containing cells provide major inhibitory innervation of thalamic relay nuclei that is critical to thalamocortical rhythm generation

(dis)inhibition of thalamocortical relay neurons

Intrathalamic sensory connections mediated by the thalamic reticular nucleus --- It is proposed that, during wakefulness, TRN is crucially involved in resetting the activity levels in sensory nuclei of the dorsal thalamus, which allows the cortex to actively and periodically compare its on-going sensory processing with the available sensory information.

"We further suggest that, upon arousal, disinhibition of thalamocortical neurons (via the local-circuit neurons) outweighs direct inhibition of the thalamocortical neurons."