Abstract
A certain level of arousal is required for an individual to perform optimally, and the locus coeruleus norepinephrine (LC-NE) system plays a central role in optimizing arousal. Tonic firing of LC-NE neurons needs to be held within a narrow range of 1–3 Hz to facilitate phasic firing of the LC-NE neurons; these two modes of activity act synergistically, to allow the individual to perform attentional tasks optimally. How this information can be applied to further our understanding of psychiatric disorders has not been fully elucidated. Here we propose two models of altered LC-NE activity that result in attentional deficits characteristic of psychiatric disorders: 1) ‘hypoaroused’ individuals with e.g. attention-deficit/hyperactivity disorder (ADHD) have decreased tonic firing of the LC-NE system, resulting in decreased cortical arousal and poor attentional performance and 2) ‘hyperaroused’ individuals with e.g. anxiety disorders have increased tonic firing of the LC-NE system, resulting in increased cortical arousal and impaired attentional performance. We argue that hypoarousal (decreased tonic firing of LC-NE neurons) and hyperarousal (increased tonic firing of LC-NE neurons) are suboptimal states in which phasic activity of LC-NE neurons is impeded. To further understand the neurobiology of attentional dysfunction in psychiatric disorders a translational approach that integrates findings on the LC-NE arousal system from animal models and human imaging studies may be useful.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Background
It is commonly accepted that an individual who is ‘hypoaroused’ or ‘hyperaroused’ will not perform optimally in cognitive and behavioural tasks. This view stems from the empirical work of Yerkes and Dodson (1908) on a ‘dancing mouse’ model in which they determined the time it took for an animal to demonstrate avoidance behaviour by varying the intensity of an electrical pulse (Yerkes and Dodson 1908). These data were subsequently developed into what is commonly known as the Yerkes-Dodson theory (Winton 1987), in which performance is a function of the level of arousal. The Yerkes-Dodson theory states that for an individual to attain optimal performance on cognitive and behavioural tasks, the individual’s level of arousal needs to be held within a narrow ‘range’ (Fig. 1a). There are several central arousal systems which arise from nuclei in the brainstem (Moruzzi and Magoun 1949), one of these being the locus coeruleus-norepinephrine (LC-NE) system.
Diagrammatic representation of the first hypothesis a Yerkes and Dodson theory that relates performance to the level of arousal, as an inverted-U. b Tonic firing of LC-NE neurons needs to be held within the 1–3 Hz range, which marks the range of arousal that will allow optimal performance. c Phasic firing of the LC-NE system occurs optimally when the tonic firing of the LC is within the 1–3 Hz range
The LC-NE system is the sole source of norepinephrine (NE) in the cortex (Aston-Jones et al. 1999; Bunsey and Strupp 1995; Foote et al. 1980; Jentsch 2005; Southwick et al. 1999). LC-NE neurons can be distinguished by their characteristic tonic and phasic modes of firing. Tonic firing of LC-NE neurons can in turn be identified by its diurnal variation of activity, which is related to the state of cortical arousal of the individual (Aston-Jones et al. 2001). Thus during alert wakefulness the LC fires tonically in a range of 1–3 Hz and is associated with increased cortical arousal, while during deep sleep the LC does not fire tonically and there is decreased cortical arousal (Aston-Jones and Bloom 1981a, b; Berridge and Foote 1991; Foote et al. 1980; McCormick and Bal 1994).
Phasic firing of LC-NE neurons occurs during processes that involve attention, such as those required to perform voluntary behavior. Attention was early on elegantly described by William James as “taking possession by the mind in clear and vivid form, from one out of what seems several simultaneously possible objects or trains of thought” (James 1890). This description of active attention has been further developed to describe the individual processes that are required: (1) alerting, (2) orienting, and (3) executive control (Coull 1998; Posner et al. 2006). The LC-NE system plays a particularly important role in alerting and orienting; for example when a new stimulus is presented, the firing rate of LC-NE neurons changes from tonic firing to phasic bursts of activity, which enhance the ‘signal’ to ‘noise’ ratio. The tonic activity of the LC-NE system is then resumed after a refractory period (Aston-Jones and Bloom 1981a, b; Aston-Jones et al. 1991a, b; 1997; Bouret and Sara 2005; Grant et al. 1988; Rajkowski et al. 1994; Sara et al. 1995).
Attentional processes are reflected in electrophysiological recordings of electroencephalographic (EEG) event-related potentials (ERPs), specifically the P300 wave component. The production of the P300 is considered to reflect phasic activity of the LC-NE system (Nieuwenhuis et al. 2005). Lesions of the LC have been shown to decrease the amplitude of the P300 (Pineda and Westerfield 1993). The P300 is one of the distinct positive wave components, occurring approximately 300 msec post stimulus presentation, in the ERP waveform. The P300 is in turn comprised of fronto-central P3a and the parietal P3b components. The P3a has been strongly associated with ‘orientating’ responses, i.e. occurs predominantly in response to novelty and infrequent stimuli. The P3a then dissipates leaving the P3b component (Courchesne et al. 1975; Yamaguchi and Knight 1991), which has been strongly associated with ‘cortical updating’, i.e. the cortical representation of a task is updated continuously during each trial (Donchin and Coles 1988; Sokolov 1960; 1963).
Although the production of the P300 wave component reflects phasic activity of the LC-NE system, it is also affected by tonic activity of this system. Thus, the extent to which an individual updates the cortical representation of a task is dependent not only on changes in level of arousal over a time scale of seconds to minutes (phasic), but also on changes in arousal over a time scale from minutes to hours (tonic) (Hockey 1986; Hockey 1983; Polich and Kok 1995) The intensity of phasic LC firing has been related to cortical updating when valuable information and novelty are being processed (Aston-Jones et al. 1997; Foote et al. 1980). These data support the requirement for synergy between tonic and phasic modes of LC-NE firing for optimal performance, during tasks that require attention.
HYPOTHESIS 1: Balance between tonic and phasic firing of the LC-NE system permits optimal performance during tasks that require attention
From the above data we propose the following: (1) Optimal performance occurs when arousal is optimal, as per Yerkes and Dodson’s theory (Winton 1987) (Fig. 1a). (2) Tonic firing of the LC-NE arousal system needs to be held within the range of 1–3 Hz to facilitate optimal arousal (Fig. 1b). (3) Phasic firing of the LC-NE neurons occurs when tonic firing of the LC is held within the 1–3 Hz range, this results in optimal attentional performance (Fig. 1c). The release of NE in the cortex, through phasic activity of LC-NE neurons has been shown to enhance the ‘signal’ to ‘noise’ ratio (Berridge and Foote 1994; Moxon et al. 2007; Waterhouse and Woodward 1980). Thus, orientation to a new stimulus requires suppression of non-informative information and enhancement of relevant information processing, which is achieved through synergistic tonic and phasic firing of LC-NE arousal system.
Despite the extensive empirical evidence relating the LC-NE system to arousal and attention in electrophysiological experiments in animals and humans, the application of these data to models of psychiatric disorders that present with dysfunction in arousal and attention has not yet been fully undertaken. Here we develop the hypothesis that integration of tonic and phasic firing of the LC-NE system is needed for optimal performance, by considering empirical evidence on the activity of the LC-NE system in the context of dysfunctional arousal and attention.
HYPOTHESIS 2: Attention-deficit/hyperactivity disorder is a model of ‘hypoarousal’ resulting from decreased tonic activity of the LC-NE system
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders (Skounti et al. 2007). The main characteristics of ADHD include inability to sustain attention, impulsivity, and hyperactivity (Barkley 1997; Maedgen and Carlson 2000). ADHD has also been associated with conduct disorder and oppositional defiant disorder (Maedgen and Carlson 2000; Solanto et al. 2009). ADHD has been associated with decreased arousal, as measured peripherally by decreased skin conductance (Beauchaine et al. 2001; O'Connell et al. 2004). ADHD has also been associated with conduct disorder and oppositional defiant disorder (Maedgen and Carlson 2000; Solanto et al. 2009). There is much controversy regarding the diagnosis/subtyping of ADHD, including the under diagnosis of childhood post-traumatic stress disorder which presents with similar behavioural attributes, however the individual suffering from post-traumatic stress disorder is ‘hyperaroused’ and presents with avoidance behaviours, a key feature of anxiety disorders (Weinstein et al. 2000). Furthermore, cortical hypoarousal in ADHD is reflected in increased low frequency/decreased high frequency spontaneous cortical activity (i.e. increased cortical theta (θ, 4–7 Hz) band power and decreased cortical beta (β, 15–30 Hz) band power) (Clarke et al. 2001, 2002, 2007).
Indirect evidence of disrupted tonic and phasic activity of the LC-NE system in ADHD comes from ERP studies showing reduced amplitude of the P300 component of the EEG (Alexander et al. 2008), specifically over the parietal cortex (Johnstone and Barry 1996; Lazzaro et al. 2001) during performance of a cognitive (auditory odd-ball) task. In addition, individuals with ADHD showed increased fronto-central P300 amplitudes in response to a novel target (e.g. in response to no-go targets) (Wild-Wall et al. 2009). Similar findings have been reported for individuals with schizophrenia or individuals who are psychopathic (Kiehl et al. 2000). Both studies assigned the increased fronto-central P300 amplitude to decreased cortical inhibition of frontal attentional networks (Kiehl et al. 2000; Wild-Wall et al. 2009), which similarly suggests dysfunctional regulation of frontal neurons by the LC-NE system. This may account for the variability in performance by these individuals resulting from their increased fronto-central P3a amplitude (associated with ‘orientating’ responses) during experience of the novelty of the task to the decreased parietal P3b amplitude (associated with cortical updating) due to the monotony of the task and an inability to maintain a cortical representation required from the task.
Reduced tonic activity of the LC-NE system as measured by decreased cortical arousal may result in ineffectual phasic firing of the LC-NE system. Decreased synergy between tonic and phasic firing of LC-NE neurons may account for the impulsivity in individuals with ADHD, as measured by their inability to withhold or inhibit a response (Aron and Poldrack 2005). Individuals with ADHD appear to respond reflexively (Beauchaine et al. 2001; O'Connell et al. 2004) and are unable to expend sufficient effort or increase the level of cortical arousal necessary to reduce impulsivity and maintain attention through enhancement of their level of arousal (Beauchaine et al. 2001; Howells et al. 2010; O'Connell et al. 2004).
A widely used animal model of ADHD is the spontaneously hypertensive rat (SHR). SHR was initially developed from the Wistar-Kyoto rat (WKY) for the study of adult hypertension (Okamoto and Aoki 1963). This adult hypertension is a persistent characteristic of the strain (152 ± 6 mmHg) in comparison to its ‘standard’ normotensive control, Wistar-Kyoto rat (WKY, 102 ± 4 mmHg) (Kaehler et al. 2004; Singewald et al. 2000). In later years the SHR was found to exhibit characteristics of ADHD-C (Howells et al. 2009; Kaehler et al. 2004; Knardahl and Sagvolden 1979; Rogers et al. 1988; Wultz et al. 1990). These characteristics include poor sustained attention, as measured by errors in commission and omission, and high levels of impulsivity, as measured by increased exploratory behaviour and decreased anxiety-like behaviours. In addition, SHR have increased locomotor activity, particularly during pre-adolescence, comparative with the presentation of ADHD in children (Howells et al. 2009; Marti and Armario 1996; van den Bergh et al. 2006).
Empirical evidence supports dysfunctional regulation of tonic and phasic modes of firing of the LC-NE system in SHR. Attentional performance in SHR is improved by psychostimulant treatment, which increases the extracellular concentration of NE (Sagvolden et al. 1992; Wultz et al. 1990). Furthermore α2-adrenoreceptor (presynaptic autoreceptors that attenuate the release of NE) function is reduced in SHR (Russell et al. 2000; Russell and Wiggins 2000; Tsuda et al. 1994), and expression of α2-adrenoreceptors is reduced (Olmos et al. 1991). Drugs that are effective in improving attentional performance either primarily increase extracellular NE concentrations (Sagvolden et al. 1992) or improve autoreceptor function, such as was found after treatment with an α2-adrenoreceptor agonist, guanfacine (Sagvolden 2006). Decreased autoreceptor function has been related to the behavioural characteristics of SHR (Howells et al. 2009; Leibowitz et al. 1989; Reyes et al. 2006; Valentino and Van Bockstaele 2008). These data indicate that SHR have decreased extracellular concentrations of NE and suggest low tonic LC-NE firing. This may account for poor attentional performance as locally released glutamate-stimulated release of NE, through either direct infusion of glutamate or a behavioural stressor, is greater in SHR than in several control rat strains and for several brain areas (Howells and Russell 2008; Howells et al. 2009; Kaehler et al. 2004; Kawasaki et al. 1991; Leibowitz et al. 1989; Reyes et al. 2006; Russell et al. 2000; Russell and Wiggins 2000; Singewald et al. 2000; Valentino and Van Bockstaele 2008). This increased stimulated release of NE is possibly compensatory; we suggest that it is a result of low tonic firing of LC-NE neurons.
From the above data we propose: (1) Individuals who are ‘hypoaroused’ (i.e. individuals with ADHD and the SHR a widely accepted animal model of ADHD) will perform poorly in tasks that require attention. (2) Tonic firing of the LC-NE arousal system in such individuals is low or decreased, not held within the optimal range of 1–3 Hz, during wakefulness. This results in a low level of cortical arousal. (3) When phasic firing of the LC-NE neurons occurs, enhancement of the ‘signal’ is achieved with high levels of novelty and acute stressors; however maintenance of the ‘signal’ is not achieved. This results in poor attentional performance as well as related deficits in inhibitory processes and reflexive responding (Fig. 2).
Diagrammatic representation of the second hypothesis. Individuals that are ‘hypoaroused’ do not perform optimally (left side of inverted-U), tonic firing of the LC-NE system is low or decreased and not held within the 1–3 Hz range during wakefulness (left pointing arrows), when phasic firing of the LC occurs, optimal behavioural performance is not possible and the individuals appear inattentive and impulsive
HYPOTHESIS 3: Anxiety disorders as a model of ‘hyperarousal’ resulting from increased tonic activity of the LC-NE system
Anxiety disorders are the most prevalent psychiatric disorders in community studies (Kessler et al. 2007; Wittchen and Jacobi 2005). The anxiety disorders share a common clinical characteristic; they all present with excessive avoidance behaviours (Mineka and Zinbarg 2006). Excessive avoidance behaviours are in turn reflected in deficits in attention, as measured by increased arousal in response to target stimuli that overwhelms attentional networks and leads to errors of omission (Castaneda et al. 2008; Li et al. 2011; Waters et al. 2009). Cortical hyperarousal in individuals with anxiety disorders can be identified by decreased low frequency/increased high frequency spontaneous cortical activity (i.e. decreased cortical theta (θ, 4–7 Hz) band power and increased cortical beta (β, 15–30 Hz) band power) (Buchsbaum et al. 1985; Grin-Yatsenko et al. 2009, 2010; Matousek 1991).
Indirect evidence of altered tonic and phasic modes of LC-NE activity is derived from ERP studies of individuals with anxiety disorders which show reduced amplitude of the parietal P300 component (Bauer et al. 2001; Boudarene and Timsit-Berthier 1997). Individuals with anxiety disorders show deficits in the P300 wave component (decreased P300 amplitude) during presentation of target stimuli, but increased P300 amplitude during non-target information processing. The level of information processing is greater than the response to target stimuli (increased P300 amplitude) (Li et al. 2011). Peripheral information is given greater importance than the ‘signal’, with ineffectual suppression of the ‘noise’ and decreased attentional performance.
A range of findings points towards dysfunction of the LC-NE system in the anxiety disorders. Disrupted ultrastructure of the LC-NE nucleus, decreased neuron counts, increased α2-adrenoreceptor expression and sensitivity, and down-regulation of NE re-uptake transporters have for example been reported in post-mortem studies of individuals with anxiety disorders (Arango et al. 1996; Baumann et al. 1999; Bracha et al. 2005; Issidorides 1990; Klimek et al. 1997; Ordway et al. 2003; Southwick et al. 1999). These data suggest that the LC-NE system may have been down-regulated in an attempt to compensate for the lack of negative feedback required to re-establish synergy between the tonic and phasic modes of firing of LC-NE neurons by decreasing tonic activity.
The Wistar Kyoto rat (WKY/NCrl) has been proposed as a model of anxiety disorders (Jiao et al. 2011; McAuley et al. 2009). Indeed this strain has been used for several years as the comparator strain for SHR (Okamoto and Aoki 1963). However, when WKY animals were compared to other rat strains it became apparent that they also had deficits in attentional performance (Roessner et al. 2010; Sagvolden et al. 2009). Attentional performance deficits, or errors of omission, in WKY rats are, however, related to increased avoidance behaviours, as measured by decreased exploratory behaviour, increased anxiety-like behaviours, and decreased locomotor activity (Armario et al. 1995; Baum et al. 2006; Braw et al. 2006; Howells et al. 2009; Lahmame et al. 1997; Malkesman et al. 2005; Marti and Armario 1996; Pardon et al. 2002; Ramos et al. 1997; Sagvolden et al. 1993; Sukhanov et al. 2004; Tejani-Butt et al. 2003).
Empirical evidence supports dysfunctional regulation of tonic and phasic modes of firing of LC-NE neurons in WKY. Attentional performance of WKY is improved by enhancing extracellular concentrations of NE by blocking NE reuptake and stimulating α2-adrenoreceptors (Tejani-Butt et al. 2003). NE release from LC-NE neurons stimulated by either direct infusion of glutamate or a behavioural stressor is decreased in WKY (Pardon et al. 2002).
From the above data we propose (1) individuals who are ‘hyperaroused’ (i.e. individuals with anxiety disorders and the WKY a promising model of anxiety disorders) perform poorly on tasks of attention. (2) Tonic firing of the LC-NE arousal system in such individuals is high or increased, not being held within the optimal 1–3 Hz range during wakefulness. This results in a high level of cortical arousal and perpetuation of hypothalamic pituitary axis activity. (3) When phasic firing of the LC-NE neurons occurs, enhancement of the ‘signal’ and suppression of ‘noise’ is not effectual, as high tonic levels of NE may have down-regulated postsynaptic β-adrenoceptors. Poor attentional performance is evidenced in part by avoidance behaviours, and there is an absence or attenuated response of the LC-NE system to novelty and stressors (Lukaszewska and Niewiadomska 1995) (Fig. 3).
Diagrammatic representation of the third hypothesis. Individuals that are ‘hyperaroused’ do not perform optimally (right side of inverted-U), tonic firing of the LC-NE system is higher or increased and not held within the 1–3 Hz range during wakefulness (right pointing arrows), when phasic firing of the LC occurs optimal behavioural performance is not possible and the individuals appear inattentive and display avoidant behaviours
Conclusions and implications
In the present paper, we propose a model of the LC-NE arousal system that explains deficits in attentional performance in individuals with different psychiatric disorders. The LC-NE system fires in two modes, tonic and phasic. These two modes of firing need to work synergistically. We propose that ADHD, a disorder of ‘hypoarousal’, presents with low tonic firing of the LC-NE system while anxiety disorders, conditions characterized by ‘hyperarousal’, present with high tonic firing of the LC-NE system. Either low or high tonic firing of the LC-NE system results in ineffectual phasic activity of the LC-NE system and results in attentional deficits and poor performance.
We would argue that these hypotheses allow an integration of data from multiple studies, including both human and animal research. The implications of the proposed hypotheses address several methodological aspects that have been negated in attempts to understand the attentional dysfunctions in the psychiatric disorders. (1) The neurophysiology of psychiatric disorders including the electrical signatures and neurochemical signatures should not be looked at in isolation. (2) We are now able to conceptualize the interactions between state (tonic) and trait (phasic) aspects of electrical and neurochemical properties of these systems, afforded by brain imaging techniques in humans and with the use of well characterized animal models of the disorder in study. We suggest that this integrative approach, albeit non-linear, is capable of providing greater insight to psychiatric disorders, and may serve as the next step in moving forward our understanding of the neurobiology of psychiatric disorders, including their attentional dysfunction. We hope that this paper provides some impetus for that work to succeed.
References
Alexander DM, Hermens DF, Keage HA, Clark CR, Williams LM, Kohn MR, Clarke SD, Lamb C, Gordon E (2008) Event-related wave activity in the EEG provides new marker of ADHD. Clin Neurophysiol 119:163–179
Arango V, Underwood MD, Mann JJ (1996) Fewer pigmented locus coeruleus neurons in suicide victims: preliminary results. Biol Psychiatry 39:112–120
Armario A, Gavalda A, Marti J (1995) Comparison of the behavioural and endocrine response to forced swimming stress in five inbred strains of rats. Psychoneuroendocrinology 20:879–890
Aron AR, Poldrack RA (2005) The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1285–1292
Aston-Jones G, Bloom FE (1981a) Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J Neurosci 1:887–900
Aston-Jones G, Bloom FE (1981b) Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci 1:876–886
Aston-Jones G, Chiang C, Alexinsky T (1991a) Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance. Prog Brain Res 88:501–520
Aston-Jones G, Shipley MT, Chouvet G, Ennis M, van Bockstaele E, Pieribone V, Shiekhattar R, Akaoka H, Drolet G, Astier B (1991b) Afferent regulation of locus coeruleus neurons: anatomy, physiology and pharmacology. Prog Brain Res 88:47–75
Aston-Jones G, Rajkowski J, Kubiak P (1997) Conditioned responses of monkey locus coeruleus neurons anticipate acquisition of discriminative behavior in a vigilance task. Neuroscience 80:697–715
Aston-Jones G, Rajkowski J, Cohen J (1999) Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 46:1309–1320
Aston-Jones G, Chen S, Zhu Y, Oshinsky ML (2001) A neural circuit for circadian regulation of arousal. Nat Neurosci 4:732–738
Barkley RA (1997) Advancing age, declining ADHD. Am J Psychiatry 154:1323–1325
Bauer LO, Costa L, Hesselbrock VM (2001) Effects of alcoholism, anxiety and depression on P300 in women: a pilot study. J Stud Alcohol 62:571–579
Baum AE, Solberg LC, Churchill GA, Ahmadiyeh N, Takahashi JS, Redei EE (2006) Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality. Behav Brain Res 169:220–230
Baumann B, Danos P, Krell D, Diekmann S, Wurthmann C, Bielau H, Bernstein HG, Bogerts B (1999) Unipolar-bipolar dichotomy of mood disorders is supported by noradrenergic brainstem system morphology. J Affect Disord 54:217–224
Beauchaine TP, Katkin ES, Strassberg Z, Snarr J (2001) Disinhibitory psychopathology in male adolescents: discriminating conduct disorder from attention-deficit/hyperactivity disorder through concurrent assessment of multiple autonomic states. J Abnorm Psychol 110:610–624
Berridge CW, Foote SL (1991) Effects of locus coeruleus activation on electroencephalographic activity in neocortex and hippocampus. J Neurosci 11:3135–3145
Berridge CW, Foote SL (1994) Locus coeruleus-induced modulation of forebrain electroencephalographic (EEG) state in halothane-anesthetized rat. Brain Res Bull 35:597–605
Boudarene M, Timsit-Berthier M (1997) Stress, anxiety and event related potentials. Encephale 23:237–250
Bouret S, Sara SJ (2005) Network reset: a simplified overarching theory of locus coeruleus noradrenaline function. Trends Neurosci 28:574–582
Bracha HS, Garcia-Rill E, Mrak RE, Skinner R (2005) Postmortem locus coeruleus neuron count in three American veterans with probable or possible war-related PTSD. J Neuropsychiatry Clin Neurosci 17:503–509
Braw Y, Malkesman O, Dagan M, Bercovich A, Lavi-Avnon Y, Schroeder M, Overstreet DH, Weller A (2006) Anxiety-like behaviors in pre-pubertal rats of the flinders sensitive line (FSL) and Wistar-Kyoto (WKY) animal models of depression. Behav Brain Res 167:261–269
Buchsbaum MS, Hazlett E, Sicotte N, Stein M, Wu J, Zetin M (1985) Topographic EEG changes with benzodiazepine administration in generalized anxiety disorder. Biol Psychiatry 20:832–842
Bunsey MD, Strupp BJ (1995) Specific effects of idazoxan in a distraction task: evidence that endogenous norepinephrine plays a role in selective attention in rats. Behav Neurosci 109:903–911
Castaneda AE, Tuulio-Henriksson A, Marttunen M, Suvisaari J, Lönnqvist J (2008) A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. J Affect Disord 106:1–27
Clarke AR, Barry RJ, McCarthy R, Selikowitz M (2001) EEG-defined subtypes of children with attention-deficit/hyperactivity disorder. Clin Neurophysiol 112:2098–2105
Clarke AR, Barry RJ, McCarthy R, Selikowitz M (2002) Children with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: an EEG analysis. Psychiatry Res 111:181–190
Clarke AR, Barry RJ, McCarthy R, Selikowitz M, Johnstone SJ, Hsu CI, Magee CA, Lawrence CA, Croft RJ (2007) Coherence in children with attention-Deficit/Hyperactivity disorder and excess beta activity in their EEG. Clin Neurophysiol 118:1472–1479
Coull JT (1998) Neural correlates of attention and arousal: insights from electrophysiology, functional neuroimaging and psychopharmacology. Prog Neurobiol 55:343–361
Courchesne E, Hillyard SA, Galambos R (1975) Stimulus novelty, task relevance and the visual evoked potential in man. Electroencephalogr Clin Neurophysiol 39:131–143
Donchin E, Coles MGH (1988) Is the P300 component a manifestation of context updating? Behav Brain Sci 11:355–372
Foote SL, Aston-Jones G, Bloom FE (1980) Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc Natl Acad Sci U S A 77:3033–3037
Grant SJ, Aston-Jones G, Redmond DE Jr (1988) Responses of primate locus coeruleus neurons to simple and complex sensory stimuli. Brain Res Bull 21:401–410
Grin-Yatsenko VA, Baas I, Ponomarev VA, Kropotov JD (2009) EEG power spectra at early stages of depressive disorders. J Clin Neurophysiol 26:401–406
Grin-Yatsenko VA, Baas I, Ponomarev VA, Kropotov JD (2010) Independent component approach to the analysis of EEG recordings at early stages of depressive disorders. Clin Neurophysiol 121:281–289
Hockey G (1986) A state control theory of adaptation to stress and individual differences in stress management: energetics and human information processing. Nijhoff, Dordrecht
Hockey R (1983) Stress and fatigue in human performance. Wiley, Chicester
Howells FM, Russell VA (2008) Glutamate-stimulated release of norepinephrine in hippocampal slices of animal models of attention-deficit/hyperactivity disorder (spontaneously hypertensive rat) and depression/anxiety-like behaviours (Wistar-Kyoto rat). Brain Res 1200:107–115
Howells FM, Bindewald L, Russell VA (2009) Cross-fostering does not alter the neurochemistry or behavior of spontaneously hypertensive rats. Behav Brain Funct 5:24
Howells FM, Stein DJ, Russell VA (2010) Perceived mental effort correlates with changes in tonic arousal during attentional tasks. Behav Brain Funct 6:39
Issidorides MR (1990) Blood and brain relationships in schizophrenia and depression: histochemical and ultrastructural correlates: an overview. Int J Neurosci 51:351–353
James W (1980) The principles of psychology, Vol. 1. New York, New York, pp 403–404
Jentsch JD (2005) Impaired visuospatial divided attention in the spontaneously hypertensive rat. Behav Brain Res 157:323–330
Jiao X, Pang KC, Beck KD, Minor TR, Servatius RJ (2011) Avoidance perseveration during extinction training in Wistar-Kyoto rats: an interaction of innate vulnerability and stressor intensity. Behav Brain Res 221:98–107
Johnstone SJ, Barry RJ (1996) Auditory event-related potentials to a two-tone discrimination paradigm in attention deficit hyperactivity disorder. Psychiatry Res 64:179–192
Kaehler ST, Salchner P, Singewald N, Philippu A (2004) Differential amino acid transmission in the locus coeruleus of Wistar Kyoto and spontaneously hypertensive rats. Naunyn Schmiedebergs Arch Pharmacol 370:381–387
Kawasaki S, Takeda K, Tanaka M, Itoh H, Hirata M, Nakata T, Hayashi J, Oguro M, Sasaki S, Nakagawa M (1991) Enhanced norepinephrine release in hypothalamus from locus coeruleus in SHR. Jpn Heart J 32:255–262
Kessler RC, Angermeyer M, Anthony JC, De Graaf R, Demyttenaere K, Gasquet I, De Girolamo G, Gluzman S, Gureje O, Haro JM, Kawakami N, Karam A, Levinson D, Medina Mora ME, Oakley Browne MA, Posada-Villa J, Stein DJ, Adley Tsang CH, Aguilar-Gaxiola S, Alonso J, Lee S, Heeringa S, Pennell BE, Berglund P, Gruber MJ, Petukhova M, Chatterji S, Ustun TB (2007) Lifetime prevalence and age-of-onset distributions of mental disorders in the world health organization's world mental health survey initiative. World Psychiatry 6:168–176
Kiehl KA, Smith AM, Hare RD, Liddle PF (2000) An event-related potential investigation of response inhibition in schizophrenia and psychopathy. Biol Psychiatry 48:210–221
Klimek V, Stockmeier C, Overholser J, Meltzer HY, Kalka S, Dilley G, Ordway GA (1997) Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci 17:8451–8458
Knardahl S, Sagvolden T (1979) Open-field behavior of spontaneously hypertensive rats. Behav Neural Biol 27:187–200
Lahmame A, Grigoriadis DE, De Souza EB, Armario A (1997) Brain corticotropin-releasing factor immunoreactivity and receptors in five inbred rat strains: relationship to forced swimming behaviour. Brain Res 750:285–292
Lazzaro I, Gordon E, Whitmont S, Meares R, Clarke S (2001) The modulation of late component event related potentials by pre-stimulus EEG theta activity in ADHD. Int J Neurosci 107:247–264
Leibowitz SF, Diaz S, Tempel D (1989) Norepinephrine in the paraventricular nucleus stimulates corticosterone release. Brain Res 496:219–227
Li Y, Hu Y, Liu T, Wu D (2011) Dipole source analysis of auditory P300 response in depressive and anxiety disorders. Cogn Neurodyn 5:221–229
Lukaszewska I, Niewiadomska G (1995) The differences in learning abilities between spontaneously hypertensive (SHR) and Wistar normotensive rats are cue dependent. Neurobiol Learn Mem 63:43–53
Maedgen JW, Carlson CL (2000) Social functioning and emotional regulation in the attention deficit hyperactivity disorder subtypes. J Clin Child Psychol 29:30–42
Malkesman O, Braw Y, Zagoory-Sharon O, Golan O, Lavi-Avnon Y, Schroeder M, Overstreet DH, Yadid G, Weller A (2005) Reward and anxiety in genetic animal models of childhood depression. Behav Brain Res 164:1–10
Marti J, Armario A (1996) Forced swimming behavior is not related to the corticosterone levels achieved in the test: a study with four inbred rat strains. Physiol Behav 59:369–373
Matousek M (1991) EEG patterns in various subgroups of endogenous depression. Int J Psychophysiol 10:239–243
McAuley JD, Stewart AL, Webber ES, Cromwell HC, Servatius RJ, Pang KC (2009) Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis. Behav Brain Res 204:162–168
McCormick DA, Bal T (1994) Sensory gating mechanisms of the thalamus. Curr Opin Neurobiol 4:550–556
Mineka S, Zinbarg R (2006) A contemporary learning theory perspective on the etiology of anxiety disorders: it's not what you thought it was. Am Psychol 61:10–26
Moruzzi G, Magoun HW (1949) Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1:455–473
Moxon KA, Devilbiss DM, Chapin JK, Waterhouse BD (2007) Influence of norepinephrine on somatosensory neuronal responses in the rat thalamus: a combined modeling and in vivo multi-channel, multi-neuron recording study. Brain Res 1147:105–123
Nieuwenhuis S, Aston-Jones G, Cohen JD (2005) Decision making, the P3, and the locus coeruleus-norepinephrine system. Psychol Bull 131:510–532
O'Connell RG, Bellgrove MA, Dockree PM, Robertson IH (2004) Reduced electrodermal response to errors predicts poor sustained attention performance in attention deficit hyperactivity disorder. Neuroreport 15:2535–2538
Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282–293
Olmos G, Miralles A, Barturen F, Garcia-Sevilla JA (1991) Decreased density and sensitivity of alpha 2-adrenoceptors in the brain of spontaneously hypertensive rats. Eur J Pharmacol 205:93–96
Ordway GA, Schenk J, Stockmeier CA, May W, Klimek V (2003) Elevated agonist binding to alpha2-adrenoceptors in the locus coeruleus in major depression. Biol Psychiatry 53:315–323
Pardon MC, Gould GG, Garcia A, Phillips L, Cook MC, Miller SA, Mason PA, Morilak DA (2002) Stress reactivity of the brain noradrenergic system in three rat strains differing in their neuroendocrine and behavioral responses to stress: implications for susceptibility to stress-related neuropsychiatric disorders. Neuroscience 115:229–242
Pineda JA, Westerfield M (1993) Monkey P3 in an "oddball" paradigm: pharmacological support for multiple neural sources. Brain Res Bull 31:689–696
Polich J, Kok A (1995) Cognitive and biological determinants of P300: an integrative review. Biol Psychol 41:103–146
Posner MI, Sheese BE, Odludas Y, Tang Y (2006) Analyzing and shaping human attentional networks. Neural Netw 19:1422–1429
Rajkowski J, Kubiak P, Aston-Jones G (1994) Locus coeruleus activity in monkey: phasic and tonic changes are associated with altered vigilance. Brain Res Bull 35:607–616
Ramos A, Berton O, Mormede P, Chaouloff F (1997) A multiple-test study of anxiety-related behaviours in six inbred rat strains. Behav Brain Res 85:57–69
Reyes BA, Fox K, Valentino RJ, Van Bockstaele EJ (2006) Agonist-induced internalization of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Eur J Neurosci 23:2991–2998
Roessner V, Sagvolden T, DasBanerjee T, Middleton FA, Faraone SV, Walaas SI, Becker A, Rothenberger A, Bock N (2010) Methylphenidate normalizes elevated dopamine transporter densities in an animal model of the attention-deficit/hyperactivity disorder combined type, but not to the same extent in one of the attention-deficit/hyperactivity disorder inattentive type. Neuroscience 167:1183–1191
Rogers LJ, Sink HS, Hambley JW (1988) Exploration, fear and maze learning in spontaneously hypertensive and normotensive rats. Behav Neural Biol 49:222–233
Russell VA, Wiggins TM (2000) Increased glutamate-stimulated norepinephrine release from prefrontal cortex slices of spontaneously hypertensive rats. Metab Brain Dis 15:297–304
Russell V, Allie S, Wiggins T (2000) Increased noradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder–the spontaneously hypertensive rat. Behav Brain Res 117:69–74
Sagvolden T (2006) The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of attention-Deficit/Hyperactivity disorder (ADHD). Behav Brain Funct 2:41
Sagvolden T, Metzger MA, Schiorbeck HK, Rugland AL, Spinnangr I, Sagvolden G (1992) The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor stimulants. Behav Neural Biol 58:103–112
Sagvolden T, Pettersen MB, Larsen MC (1993) Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains. Physiol Behav 54:1047–1055
Sagvolden T, Johansen EB, Wøien G, Walaas SI, Storm-Mathisen J, Bergersen LH, Hvalby Ø, Jensen V, Aase H, Russell VA, Killeen PR, DasBanerjee T, Middleton FA, Faraone SV (2009) The spontaneously hypertensive rat model of ADHD—the importance of selecting the appropriate reference strain. Neuropharmacology 57:619–626
Sara SJ, Dyon-Laurent C, Herve A (1995) Novelty seeking behavior in the rat is dependent upon the integrity of the noradrenergic system. Brain Res Cogn Brain Res 2:181–187
Singewald N, Kouvelas D, Mostafa A, Sinner C, Philippu A (2000) Release of glutamate and GABA in the amygdala of conscious rats by acute stress and baroreceptor activation: differences between SHR and WKY rats. Brain Res 864:138–141
Skounti M, Philalithis A, Galanakis E (2007) Variations in prevalence of attention deficit hyperactivity disorder worldwide. Eur J Pediatr 166:117–123
Sokolov EN (1960) Neuronal models and the orienting reflex. In Brazier MAB, the central nervous system and behavior. J Macy, New York, pp 187–276
Sokolov EN (1963) Perception and the conditioned reflex. Pergamon, Oxford
Solanto MV, Schulz KP, Fan J, Tang CY, Newcorn JH (2009) Event-related FMRI of inhibitory control in the predominantly inattentive and combined subtypes of ADHD. J Neuroimaging 19:205–212
Southwick SM, Bremner JD, Rasmusson A, Morgan CA 3rd, Arnsten A, Charney DS (1999) Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry 46:1192–1204
Sukhanov IM, Zakharova ES, Danysz W, Bespalov AY (2004) Effects of NMDA receptor channel blockers, MK-801 and memantine, on locomotor activity and tolerance to delay of reward in Wistar-Kyoto and spontaneously hypertensive rats. Behav Pharmacol 15:263–271
Tejani-Butt S, Kluczynski J, Pare WP (2003) Strain-dependent modification of behavior following antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 27:7–14
Tsuda K, Tsuda S, Nishio I, Masuyama Y, Goldstein M (1994) Glutamatergic regulation of [3H]-noradrenaline release in the medulla oblongata of normotensive and spontaneously hypertensive rats. J Hypertens 12:517–522
Valentino RJ, Van Bockstaele E (2008) Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharmacol 583:194–203
van den Bergh FS, Bloemarts E, Chan JS, Groenink L, Olivier B, Oosting RS (2006) Spontaneously hypertensive rats do not predict symptoms of attention-deficit hyperactivity disorder. Pharmacol Biochem Behav 83:380–390
Waterhouse BD, Woodward DJ (1980) Interaction of norepinephrine with cerebrocortical activity evoked by stimulation of somatosensory afferent pathways in the rat. Exp Neurol 67:11–34
Waters AM, Henry J, Neumann DL (2009) Aversive pavlovian conditioning in childhood anxiety disorders: impaired response inhibition and resistance to extinction. J Abnorm Psychol 118:311–321
Weinstein D, Staffelbach D, Biaggio M (2000) Attention-deficit hyperactivity disorder and posttraumatic stress disorder: differential diagnosis in childhood sexual abuse. Clin Psychol Rev 20:359–378
Wild-Wall N, Oades RD, Schmidt-Wessels M, Christiansen H, Falkenstein M (2009) Neural activity associated with executive functions in adolescents with attention-deficit/hyperactivity disorder (ADHD). Int J Psychophysiol 74:19–27
Winton WM (1987) Do introductory textbooks present the Yerkes-Dodson law correctly? Am Psychol 42:202–203
Wittchen HU, Jacobi F (2005) Size and burden of mental disorders in europe–a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 15:357–376
Wultz B, Sagvolden T, Moser EI, Moser MB (1990) The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior. Behav Neural Biol 53:88–102
Yamaguchi S, Knight RT (1991) Age effects on the P300 to novel somatosensory stimuli. Electroencephalogr Clin Neurophysiol 78:297–301
Yerkes RM, Dodson JD (1908) The relation of strength of stimulus to rapidity of habit-formation. J Comp Neurol Psychol 18:459–482
Acknowledgements
The authors would like to thank the South African Medical Research Council and the University of Cape Town for financial support. This work formed part of the PhD thesis of FMH.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Howells, F.M., Stein, D.J. & Russell, V.A. Synergistic tonic and phasic activity of the locus coeruleus norepinephrine (LC-NE) arousal system is required for optimal attentional performance. Metab Brain Dis 27, 267–274 (2012). https://doi.org/10.1007/s11011-012-9287-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-012-9287-9