Sie sind auf Seite 1von 8

The Neurobiology of ADHD (printer-friendly)

The Experience of Attention

Attention is a lot like love. Everyone knows what it is and when it's present, but the multiple components of attention defy easy definition. Attention is the thread that holds together the fabric of our consciousness. For all we know about brain function, the greatest mystery is consciousness itself. How are we aware of what we perceive? How do we know what we know? Attention encompasses the process that allows us to focus on what is important and to filter out what is trivial. Much of this process occurs preconsciously, without effort or awareness. Voluntary attention links the thoughts and emotions we consciously choose to focus on. Because it operates at such a basic level, the process that regulates attention must be very connected to a fundamental sense of self. How we focus our thoughts and feelings is a major expression of self. We ponder what is the "I" that directs our attention.

We know that neurotransmitters such as dopamine and norepinephrine are critical to the language of attention, providing the means of the communication of information across synapses vital to alertness and focus, prerequisites to content. But where, and on what brain systems, do these neurotransmitters operate?

While the nature of attention has been widely discussed, there is a need for an integrative analyses, which is offered here. [1-3]

Components of Attention

To understand attention, one must first deconstruct its components. A process as complex as attention is not one process but many processes acting in concert. Attention must encompass at least these components:

Arousal and alertness -- the prerequisites to attention

External or receptive attention: sensory processing and interpretation -- as with reading

Internal or reflective attention which includes thinking about ideas, concepts, and organization of projects or tasks

Processing attention or selective attention. This includes:

A. Focus -- tuning in to an object or topic

B. Filtering -- signal:noise gradient -- enhancement or activation of relevant stimuli

C. Inhibition of sensation (sensory inhibition) -- selective sensory input

External or expressive attention -- encompasses what we choose to communicate or suppress, which also evokes components of focusing, filtering, and inhibition.

Working memory -- accessing the retrieval and storage of working memory, ie, the flow of information, the content of active thought

The Process of Attention

Consider the process of landing an aircraft, which has been studied extensively in terms of altitude variables, flight safety issues, [4] and the layout of instruments on the flight panel. [5] However, it is an interesting example in terms of attention because throughout the process of flying, a pilot's attention is alternatively proactive and responsive. The pilot has to maintain an automatic scan between the instruments that identify his current position in terms of pitch (climbing or descending), roll (turning), and horizontal/lateral (direction) axes. He must also track the gradual descent of altitude. In addition, air traffic control may alter his flight path to accommodate other aircraft in the landing pattern and in response to runway availability and wind direction on the ground. All of these accommodations are also made in a context of weather conditions, in order, for example, to avoid thunderstorms and minimize turbulence. But the pilot must also monitor the plane's internal conditions -- the power settings, manifold pressure, and fuel levels. In flight, the pilot must continuously shift attention to monitor the location and functioning of the plane using the internal flight instruments, and modify it if directions from air traffic control, ambient weather, or other nearby aircraft warrant it. Mastering an automatic scan between the instruments that identify the plane's direction, pitch (up for climb; down for descent), tilt (wings level or rotated), and air speed is an essential component of flight training. Finally, as the runway comes into sight, the pilot shifts his attention towards monitoring the craft visually, in relation to the touchdown markings on the runway.

As a pilot charts the course, he varies altitude, position and speed depending on location and direction from air traffic control. His principle source of information, the object of his attention, shifts from visually monitoring the instruments to auditory interactions with air traffic control.

The Neurobiology of ADHD (printer-friendly)

His cognitive set shifts in response to the varying priorities of changes in altitude, fuel consumption, direction, weather, and wind conditions.

A sudden jolt or small shift in ongoing sounds may immediately demand a change of attention, either to weather conditions or engine

performance. The priority of his attention shifts from internal instruments to external environment, from the cockpit to the runway, from auditory to visual, as he maintains and sustains a 3-dimensional picture of location and situation. Often a pilot has to override his strong tactile (proprioceptive) sensation, such as when the instruments tell him that he is descending to the left and his body feels as if he is climbing to the right. A major risk for an amateur pilot would be to become fixated or stuck on one instrument to the neglect of essential information from other sources. When conditions change, attention must follow.

The interwoven processes of attention can be subgrouped as: (1) the prerequisites for attention, which includes adequate arousal and alertness and the organization of goal-directed purpose or interest; (2) the content of attention, which extends to sensory processing, thoughts or ideas, and memory accessing; (3)the process of attention, which involves both receptive attention and expressive attention. In both directions, attention primarily constitutes enhancing the signal:noise gradient by magnifying sensory information, emotions, or thoughts that are relevant while concurrently inhibiting stimuli that distract or interfere; (4) brain structures involved in attention, including the parts of the brain specifically involved in ADHD, like the striatum and the prefrontal cortex; (5) the modulation of attention, which includes processes that amplify or reduce attention, such as mood.

This process of deconstructing attention always runs the risk of drawing artificial boundaries between the specific cognitive processes essential to sensory or information processing and those components that specifically embody the mechanism of selection and continuity that comprise attention. [5-8]

Prerequisites of Attention

Arousal and alertness are essential to maintaining vigilance, to scanning the environment both inside the cockpit and outside the aircraft. Sensory processing of both visual and verbal information, as well as their correct interpretation, is essential in order for the pilot to determine his position, altitude, pitch, and direction. The pilot continually shifts his attention by changing focus from flight to engine

instruments, from visual to auditory information. Even though he hears conversations with all aircraft on his frequency via air traffic control, he

is constantly filtering auditory signals in order to respond only to those with his call letters, 864JWN (Juliet, Whisky, November). One of the

tasks of a pilot is to be highly selective in the information he transmits to flight control, thus exemplifying selective expression. He must inhibit his response to both extraneous instructions directed to other aircraft and unessential information that would clutter the airways and consume valuable air traffic control time. Much of initial flight training addresses communication that is highly effective and teaching a would-be pilot to provide only ended responses to direction and inhibit unnecessary chatter. All of these processes consume working memory, which is capacity-limited by how much information one can hold in memory at one moment (such as the length of digit span forward or backwards).

Effective attention requires sufficient alertness to mobilize filtering and sustain connection and interpretation of information. The ability to pay attention depends on maintaining adequate arousal to support adequate alertness in order to process information effectively. It is hard to sustain attention when we are fatigued or depressed. Attention involves emotion as well as cognition and reflects the sensorial strength of the external stimulus and the salience or degree of interest a person has.

At many levels, attention is like a dance requiring the coordination of cortical and subcortical functioning. [9] Spatial attention, for example, involves subcortical modulation of sensory experience. [10]

The neurobiological substrate of arousal encompasses several brain systems. The most critical structures for maintaining alertness include the reticular activating system. This system, beginning in the brain stem, is primarily activated by norepinephrine (NE) arousing from the locus coeruleus (LC) located in the area of the pons. The LC sends diffuse projections throughout the cortex and cerebellum, extending to the limbic system and down the spinal cord. These projections regulate both tonic (baseline) level of arousal and phasic (episodic) or event-activated arousal. [11-13] Tonic arousal helps us to stay awake while driving at night, even when we are tired. Phasic arousal is activated when the traffic suddenly stops on the freeway, and when, facilitated by a sudden NE surge, are able to quickly slam on the brakes and swerve.

Orientation. This NE surge, or burst of energy, enables us to orient to a situation, respond immediately, ie, to come "alive" and react quickly. The diffuse localization of NE neurons facilitates this broad impact on behavior and thought essential for survival in the jungle, or in an environment filled with surprise and danger. The spatial localization of events essential to orientation involves the parietal lobe.

Sensory Attention: Working Memory Arousal, Filtering, Inhibition

The Neurobiology of ADHD (printer-friendly)

is also essential in auditory attention when we are engaged in conversation or are listening to a symphony.

The extent to which we must apply effortful attention depends in part on the characteristics of the stimulus -- whether the stimulus or object of our attention is interesting, colorful, and intrinsically engages our curiosity. The cognitive effort for discrimination partially depends on how distinct the relevant stimuli are from background noise. It is much easier to process information that is moving, changing, and multisensory, such as watching TV or a movie. The attentional burden greatly increases if the stimulus is static, black on white, and does not come to life until we pay attention to it. No wonder many more people would rather see the movie than read the book! In an age of multisensory stimulation and omnipresent entertainment, shifting attention internally towards quiet contemplation or values formation or personal goals and strategies, or even internal problem solving, becomes more difficult. [6]

Inhibition. Our ability to selectively ignore repetitive or nonessential stimuli begins at the sensory, subcortical, and preconscious levels. Our capacity to listen carefully and selectively, to focus on a quiet but informative conversation in a noisy room, for example, requires noradrenergically mediated auditory discrimination.

Our internal emotional state colors the way we process information. [14] When we are depressed, our sensory sensitivity may be dampened and we may more often notice the objects that fit our mood. Similarly, anxiety can also blunt attention by preempting our focus by our internal anxiety, leading to distraction. [15]

Interest. Our ability to pay attention also depends on personal characteristics, such as our degree of alertness, our subjective interest in the subject, and the importance or motivation it has for us at the moment. We often pay attention to stimuli that are not intrinsically engaging, but which reflect our sense of purpose, priority, and importance. For example, we pay attention to taxes, even if we do not find the process or stimuli intrinsically interesting. A premed student may focus intensely on learning organic chemistry even if he or she is bored by the subject.

The Processes of Attention

This process of sensory-emotional filtering occurs at several levels: peripherally at the sensory level, and centrally at the more interpretive level. Objects in the visual sensory environment automatically potentiate neuronal activation as implicit processing, identifiable on functional magnetic resonance imaging (fMRI). [14] The processes of focusing, interpreting, inhibiting, linking, connecting, and then storing information are all connected by the thread of attention and involve many cognitive and affective structures in the brain. For sensory stimuli, processing usually begins with the eyes and ears. The identification of form and shape involves the associative cortices; the localization of stimuli occurs in the parietal lobes; and the interpretation of their significance and relevance involves the frontal cortex. The independent auditory and visual stimuli from a single source is integrated in the dorsal temporal areas for auditory input and in the ventral temporal regions for visual stimulation. These messages are linked in the association cortices that have projections to the limbic areas for affective relevance and to the prefrontal cortex for cognitive assimilation. Stimulus sequencing in movement involves the cerebellum and the caudate lobes. [2,


Inhibitory aspects of attention. At a sensory level, the ability to inhibit distractions when we are paying attention to something else is partially cortically mediated at the frontal cortex, layers 3-4, by alpha-2a-receptors. At a behavioral level, cortical inhibition enables control of impulsive action. The ability to not speak or act impulsively is a significant component of maturation, and requires learning, often from negative experiences. While much of our learning occurs at a cortical level, considerable behavioral inhibition involves the inferior prefrontal cortex (PFC). Medications such as guanfacine and clonidine act on these presynaptic receptors to downregulate a response to distractions. [7,20-22] Damage to the frontal lobes has been associated with impaired executive function, abnormal social cognition, and even impulsive homicide. [23-25]

Reflective attention. We not only pay attention to the outside world, we focus considerable awareness on internal thoughts, feelings, and memories. Memory itself may have an affective filter: When we are happy and optimistic, we may recall and anticipate more positive experiences; when we feel depressed or anxious we may notice and recall more disheartening experiences. [2,26-28]

Executive function and attention. The ability to make effective decisions requires integrative and sustained attention. The ability to search memory, to link current sensation to immediate context and connect this experience to past memories, is the quintessential attentional task. [3] Planning and working memory are essential components of executive function. [1,2] The capacity to do what we intend requires sustain attention, even in an environment of distractions and through phases of weakening interest or mounting fatigue. [29]

The cognitive aspects of executive function are primarily located in the anterior frontal cortex, whereas spatial organization occurs more dorsally; verbal memory and organization are localized more internally. Anticipatory, or expectant waiting, aspects of executive function are managed in the cingulate gyrus. The ability to interpret visual experience -- an important component in executive learning -- is processed in the posterior visual cortex. Visual orientation is localized in the dorsal visual areas; visual features are analyzed more inferiorly. As evident on fMRI, executive function is highly vulnerable to damage from traumatic brain injury. [30] Even unilateral frontal lobectomy can disturb the ability to apply strategy and intention to behavior. [31]

Language. The greatest evolutionary progress that differentiates humans from other primates is sophistication of language and reasoning.

The Neurobiology of ADHD (printer-friendly)

Though these are clearly distinct processes, they are highly interconnected. Cortical and subcortical structures are involved in language [32,33] and reading. [34] Social cognition, our understanding of social process, includes integration of sensory visual and auditory processes, [35] with an understanding of intention linked to motivation and empathy processed in the frontal lobes. [23,24] Written language can be affected by selective epilepsy as identified by neuropsychological and neuroimaging techniques. [36]

Brain structures in attention. Where does attention begin in the brain? The answer depends on where the object of attention originates -- in the external environment or within the mind or the body. We frequently pay greatest attention to our own thoughts and emotions, which arise internally without an immediate external referent. These promptings may begin in the frontal lobes or in affective regions of the temporal lobes or limbic system. Memories may have their origins in the temporal lobes; feelings may spring from limbic centers.

Much of the generation of attention begins subcortically, in the basal ganglia, which receive projections related to internal states and also process steady-state repetitive stimuli, including speech. [37] The basal ganglia also contribute to motivation and, when excessively aroused, to anxiety. [38] In many ways, the basal ganglia, acting in concert with the anterior cingulate, function as the executive assistant to the frontal lobes. These structures process considerable automatic information whose relevance and disposition do not require conscious thought or effort, thereby reserving the prefrontal cortex for more complex and significant tasks. Patients with bilateral damage to the anterior caudate lobe have difficulty with anticipatory and sequential aspects of attention. Within the frontal lobes, those aspects of working memory (or conscious thought) that involve spatial localization are analyzed more anterior-dorsally, whereas word processing occurs more inferiorly in the dominant lateral cortex. [3] The frontal lobes, in association with the basal ganglia and anterior cingulate, are involved in shifting set or anticipation of what is next. [19] Within the visual cortex, discrimination of form and feature occur more inferiorly, whereas visual orientation is localized more dorsally. Damage to the right orbitofrontal region and excessive activity within the anterior cingulate gyrus have been associated with symptoms of OCD. [39]

As shown in single photon emission computed tomography (SPECT) brain imaging scans, when a person marshals enough attention for a task requiring sustained vigilance, there is an increase in blood flow in the frontal lobes area. [40] However, patients with attention-deficit disorder (ADD) show a relative decrease in blood flow in the inferior orbital prefrontal cortex when they attempt to perform complex attentional tasks. But when they are treated with psychostimulant medications, such as amphetamines, the sufficient blood flow needed to provide the essential oxygen and glucose necessary to enhance catecholamines and facilitate inhibition does occur.

Interest. The ability to maintain interest and to attach and sustain attention is predominately dopaminergically mediated through actions in the nucleus accumbens, the center of pleasure or reinforcement. Dopamine in the mesolimbic system is critical to the attachment of attention: to fixing, filtering, and sustaining interest, pleasure, and attention.

Interpretation. The ability to interpret the meaning and significance of an event depends on activation of anterior frontal cortical function. [41] Our ability to read social cues and develop interpersonal strategies also involves the frontal lobes. [28,31] Much of what we pay attention to is internally initiated, such as reflection or problem-solving about something not in our immediate sensory environment. This includes the ability to interpret meaning in its conceptual context, essential to the recognition of sarcasm and humor. The process of interpretation and reasoning is more noradrenergically mediated, and has links to memory as well as to visual and auditory sensory systems. Medications such as atomoxetine facilitate this higher cortical processing.

Memory is involved in many aspects of consciousness. Short-term working memory includes the active processing of current awareness in relation to prior experience stored in long-term memory. Most aspects of short-term working memory engage the anterior cingulate gyrus, whose regions of activity link to the frontal lobe as shown in the Figure.

The Neurobiology of ADHD (printer-friendly) Figure. Linked to the frontal lobe, the anterior cingulate

Figure. Linked to the frontal lobe, the anterior cingulate gyrus is engaged in the process of short-term working memory.

Long-term memory is stored in the temporal lobes. Speech and language involve many of these structures, with expressive language being located more anteriorly and receptive language more posteriorly, predominantly on the left side. The temporal lobe and Broca's area have active roles in language, with the dominate lobe (usually left side) being more engaged in word-finding; the nondominant side contributes more to prosody, the rhythmic and affective aspects of speech.

Brain Structure and Function

No designation of which brain areas perform which cognitive or affective function can be accurate or complete. Most complex tasks involve multiple functional circuits that link many structures. The cerebellum is predominantly engaged in the coordination of movement and timing, and serves as a linking and integrative system for many cortically initiated activities. This integration of timing is not limited to movement; it can extend to the cognitive and affective domain. However, selective damage to the cerebellum can produce cognitive and affective symptoms. [42]

The thalamus, a large, deep structure located in the middle of the brain, regulates many components of overall arousal and provides a reciprocal relay between multiple subcortical structures and the cortex. Given its central location, the thalamus has tremendous impact on a wide spectrum of functions, including language, mood, and depression. [43,44]

The basal ganglia, caudate, and putamen, critical to motivation and the regulation of affective intensity, provide a relay for regulation of movement. Bilateral damage to the caudate nucleus can produce symptoms of dyscontrol and impulsiveness that mimic those of a frontal lobe syndrome [38] and affect the cognitive and motor aspects of speech. [37,45] The basal ganglia act in concert with the frontal lobes in interpreting perceptual experience [6] and are associated with ritualistic social behavior in animals and in man. [5]

The temporal lobes (TL) on the dominant side contribute to language through word finding and sequencing. The nondominant TL lobes are involved with syntactic aspects of language -- rhythm and expression. The TLs are essential to visual recognition memory [46] and effective response to visual and olfactory stimuli. [28] At the tip of the TLs, bilaterally, are the amygdala, the early warning system of the brain that responds to change and assesses danger vs opportunity in the environment. In EEG studies, the amygdala is activated when a subject is shown threatening faces but not benign images. [47]

The anterior cingulate participates in many aspects of executive function and working memory, and retains information in a state of expectant alertness, such as when you are looking for a particular street sign in an unfamiliar city. It also plays an important role in sustaining vs changing expectations and shifting set, the working instructions of what to do or anticipate next.

The prefrontal cortex integrates and manages the purposeful functioning of most other brain structures, receiving input and providing reciprocal regulatory control of many brain areas. While other brain regions perform the primary processing of stimuli and information, the frontal lobes interpret and provide meaning to this experience. This is the main site of voluntary, or conscious, thought and planning. The prefrontal cortex is the chief executive center of the brain through which conscious perception of our environment occurs, and where decisions are made, not only about how to react but how to affect the world and our lives. The frontal lobes are proactive, not just reactive. They are receptive and contemplative, not just responsive or active. This is where we have our primary experience of self. The broad agenda

The Neurobiology of ADHD (printer-friendly)

of the prefrontal cortex is to facilitate living a purposeful life. Relevant integration is required to connect long-term goals with the specific actions required at the moment, and to issue the commands that turn these plans into purposeful behaviors.

Although we describe these cognitive processes sequentially, they occur virtually simultaneously. As new stimuli arise, either of sensory or internal origin, process of selection, interpretation, memory, and purposeful reasoning are activated. Given the limits of sequential language, we describe these activities as occurring in specific brain areas, but in reality they occur through neural networks involving simultaneous activation of multiple pathways and through neurotransmitters functioning in concert.

Neurochemistry and the language of attention. Three neurochemical dopamine pathways convey messages for functioning that are attentionally linked. Path 1, the energy pathway, connects the substantia nigra to the motor cortex via the basal ganglia and enhances physical energy. Path 2, the desire pathway, connects the caudate lobe to the premotor cortex via the orbital prefrontal cortex. Path 3, the pleasure pathway, connects the ventral tegmental nucleus (the origin of dopamine [DA] cell bodies) to the olfactory bulb and frontal lobes via the basal ganglia so that mental energy, drive, and a sense of pleasure are transmitted. DA facilitates desire, pleasure, and interest which contribute to sustained and selective attention. NE contributes to attention through the regulation of alertness and arousal and to cognition and executive function, which extend attention into thought.

Disruption of attention. Attention is modified and influenced by noncognitive factors that reflect other personality or psychiatric considerations that can alter the depth and breath of attention. For example, attention may be scattered by ADD, decreased by fatigue, or accelerated and disorganized during mania. Obsessive-compulsive disorder (OCD) can lead to the overfocusing of attention and lack of cognitive flexibility. During depressive episodes, the rate of information processing and the depth of attention is diminished. Anxiety can interrupt sustained attention and decrease the allocation of attention to problem-solving. Effective attention requires an optimal balance of alertness, mood, and cognitive flexibility.

Attention is not only mediated by catecholamine neurotransmitters [48] but by hormones arising from the hypothalamic-pituitary-adrenal axis. Hormones as well as neurotransmitters affect alertness and have a direct effect on DA, as is evident by changes in levels of the plasma metabolite HVA. [49] Hormonal activity occurs over a longer time frame, affecting the general neurobiological environment or substrate, whereas neurotransmitter activity is virtually instantaneous and commands momentary, specific events.

Organization and executive function. Attention is also required for the reorganization of information necessary for decision-making, priority setting, and optimal execution of decisions and strategies. The information studied the night before a test needs to be reorganized during the exam or for application to a new situation. The pilot who has practiced instrument landings "under the hood" in fair weather must be able to apply these skills if he flies through a blinding snow storm.

Many neurochemical processes and neurobiological systems are involved in reorganizing information from memory and in applying this known information to novel problem-solving. For example, during the diagnostic process, physicians must reorganize information they learned during their first 2 years of medical school to guide them to an understanding of the underlying etiology or cause of a patient's problem. In the first years of medical school, a student primarily learns about organ function and what symptoms can occur when something goes wrong. During the clinical years, this information needs to be reorganized, beginning with the symptoms which must be inferred to determine which organs are involved in he particular symptoms. Information stored in long-term memory must be accessed and reorganized using a different -- actually reversed -- system. Because similar symptoms can be caused by very different underlying medical problems (consider fever or headache), the organizational and hierarchal structure must be reconstructed, not simply reversed. The relationship between afferent input and cortical organization has been studied with magnetic stimulation. [35] The ability to reorganize and resynthesize information is a frontal cortical process that depends heavily on noradrenergic functioning in the frontal cortex. [26] The capacity to attach attention, filter information, and sustain focus is highly dopaminergic. [50] Serotonin interacts with and modulates the response of striatal D2 dopamine receptors and cross-modulates the sensitivity of NE receptors. [51] Collectively, these and other neurotransmitters facilitate the sustained link of sensation to memory and the capacity for working memory and analytic thinking.

Differentiating medications for attention. Several medications have distinct and relatively discrete effects on the spectrum of attentional processes. [52] Modafinil (Provigil) primarily increases wakefulness, a component of this arousal process, which appears to be mediated by activation of the histamine receptors. Amphetamines also increase alertness and active attachment of attention, which are prerequisites to problem-solving and reasoning. Their major sites of action are the D2 receptors located in the striatum, which has projections to the mesocortical DA regions. While the primary effect of methylphenidate is to increase DA concentration within the synapse by blocking presynaptic reuptake, amphetamines have the secondary effect of increasing NE production and release. [13] Amphetamines increase alertness and enhance signal:noise differentiation, which is essential to sensory filtering and cognitive-behavioral organization. In contrast, atomoxetine (Strattera) predominately acts to block frontal-cortical NE reuptake with limited secondary effects on frontal DA. The predominant NE effect is on executive functioning, ie, postattentional information processing. There is some preliminary evidence, in part derived from our studies (R. Hunt, unpublished data) that atomoxetine may play a beneficial role in the treatment of some forms of dyslexia, but that it has little direct effect on the process of attaching attention in ADD patients. The memory components of this process may be enhanced by medications traditionally considered to be Alzheimer's medications, including memantine HCl (Namenda).

The Neurobiology of ADHD (printer-friendly)



Mazoyer B, Zago L, Mellet E, et al. Cortical networks for working memory and executive functions sustain the conscious resting state in man. Brain Res Bull. 2001; 54:287-298. Abstract


Boussaoud D. [The planning of action: can one separate attention from intention?] Med Sci (Paris). 2003;19583-19591.


Davis G. Characteristics of attention and visual short-term memory: implications for visual interface design. Philos Transact A Math Phys Eng Sci. 2004;362:2741-2759 Abstract


Russo MB, Stetz MC, Thomas ML. Monitoring and predicting cognitive state and performance via physiological correlates of neuronal signals. Aviat Space Environ Med. 2005;76(7 suppl):C59-C63.


Baxter LR Jr. Basal ganglia systems in ritualistic social displays: reptiles and humans; function and illness. Physiol Behav. 2003;79:451-460. Abstract


Richer F, Boulet C, Maheu G, Achim A, Chouinard S. Frontal and striatal brain lesions increase susceptibility to masking in perceptual decisions. Brain Cogn. 2002;50:5090-5094.


Barkley RA. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. 2nd ed. New York: Guilford Press;



Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry. 2005;57:1215-1220. Abstract


Bennett MR, Hacker PM. Emotion and cortical-subcortical function: conceptual developments. Prog Neurobiol. 2005;75:29-52. Abstract


Weddell RA. Subcortical modulation of spatial attention including evidence that the Sprague effect extends to man. Brain Cogn. 2004;55:497-506. Abstract


Aston-Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry. 1999;46:1309-1320. Abstract


Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev. 2003;42:33-84. Abstract


Pliszka SR, McCracken JT, Maas JW. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry. 1996;35:264-272. Abstract


Schubotz RI, Yves von Cramon D. Dynamic patterns make the premotor cortex interested in objects: influence of stimulus and task revealed by fMRI. Brain Res Cogn Brain Res. 2002;14:357-369. Abstract


Biederman J, Spencer T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry.



Halpern GJ, O'Connell BE. The security circuit: a proposed construct for the central nervous system. Int J Neurosci.



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


Tesche CD, Karhu JJ. Anticipatory cerebellar responses during somatosensory omission in man. Hum Brain Mapp. 2000;9:119-142. Abstract


Ravizza SM, Ciranni MA. Contributions of the prefrontal cortex and basal ganglia to set shifting. J Cogn Neurosci. 2002;14:472-483. Abstract


Hunt RD, Mandl L, Lau S, Hughes M. Neurobiological theories of ADHD and Ritalin. In: Greenhill L, ed. Ritalin: Theory and Practice. New York: Mary Ann Leibert, Inc; 1991:267-287.


Arnsten AF, Steere JC, Hunt, RD. The contribution of alpha 2-noradrenergicmechanisms to prefrontal cortical cognitive function:

Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1996;53:448-455. Abstract


Evenden J. Impulsivity: a discussion of clinical and experimental findings. J Psychopharmacol. 1999;13:180-192. Abstract


Lough S, Hodges JR. Measuring and modifying abnormal social cognition in frontal variant fronto-temporal dementia. J Psychosom Res. 2002;53:639-646. Abstract


Lough S, Gregory C, Hodges JR. Dissociation of social cognition and executive function in frontal variant frontotemporal dementia. Neurocase. 2001;7:123-130. Abstract


Relkin N, Plum F, Mattis S, Eidelberg D, Tranel D. Impulsive homicide associated with an arachnoid cyst and unilateral frontotemporal cerebral dysfunction. Semin Clin Neuropsychiatry. 1996;1:172-183. Abstract


Young EA, Abelson JL, Cameron OG. Interaction of brain noradrenergic system and the hypothalamic-pituitary-adrenal (HPA) axis in man. Psychoneuroendocrinology. 2005;30:807-814. Abstract


Hietala J, Kuoppamaki M, Nagren K, Lehikoinen P, Syvalahti E. Effects of lorazepam administration on striatal dopamine D2 receptor binding characteristics in man--a positron emission tomography study. Psychopharmacology (Berl). 1997;132:361-365. Abstract


Soussignan R, Ehrle N, Henry A, Schaal B, Bakchine S. Dissociation of emotional processes in response to visual and olfactory stimuli following frontotemporal damage. Neurocase. 2005;11:114-128. Abstract


Pliszka SR, Carlson CAL, Swanson JM. ADHD With Comorbid Disorders: Clinical Assessment and Management. New York: Guilford Press; 1999.


Scheibel RS, Pearson DA, Faria LP, et al. An fMRI study of executive functioning after severe diffuse TBI. Brain Inj. 2003;17:919-930. Erratum in: Brain Inj. 2004;18:219-220.

The Neurobiology of ADHD (printer-friendly)

31. Goldstein LH, Bernard S, Fenwick PB, Burgess PW, McNeil J. Unilateral frontal lobectomy can produce strategy application disorder. J Neurol Neurosurg Psychiatry. 1993;56:274-276. Abstract

32. Wallesch CW, Henriksen L, Kornhuber HH, Paulson OB. Observations on regional cerebral blood flow in cortical and subcortical structures during language production in normal man. Brain Lang. 1985;25:224-233. Abstract

33. Walker-Batson D, Wendt JS, Devous MD Sr, Barton MM, Bonte FJ. A long-term follow-up case study of crossed aphasia assessed by single-photon emission tomography (SPECT), language, and neuropsychological testing. Brain Lang. 1988;33:311-322. Abstract

34. Marsh EB, Hillis AE. Cognitive and neural mechanisms underlying reading and naming: evidence from letter-by-letter reading and optic aphasia. Neurocase. 2005;11:325-337. Abstract

35. Ridding MC, Rothwell JC. Afferent input and cortical organization: a study with magnetic stimulation. Exp Brain Res. 1999;126:536-544. Abstract

36. Abreu P, Ribeiro M, Forni A, Pires I, Sousa G. Writing epilepsy: a neurophysiological, neuropsychological and neuroimaging study. Epilepsy Behav. 2005;6:463-466. Abstract

37. Pickett ER, Kuniholm E, Protopapas A, Friedman J, Lieberman P. Selective speech: motor, syntax and cognitive deficits associated with bilateral damage to the putamen and the head of the caudate nucleus: a case study. Neuropsychologia. 1998;36:173-188. Abstract

38. Petty RG, Bonner D, Mouratoglou V, Silverman M. Acute frontal lobe syndrome and dyscontrol associated with bilateral caudate nucleus infarctions. Br J Psychiatry. 1996;168:237-240. Abstract

39. Ogai M, Iyo M, Mori N, Takei N. A right orbitofrontal region and OCD symptoms: a case report. Acta Psychiatr Scand. 2005;111:74-77. Abstract

40. Amen DG. Images of Human Behavior: A Brain SPECT Atlas. Newport Beach, Calif: MindWorks Press; 2001.

41. Engelien A, Huber W, Silbersweig D, et al. The neural correlates of 'deaf-hearing' in man: conscious sensory awareness enabled by attentional modulation. Brain. 2000;123 Pt 3:532-545. Abstract

42. Paulus KS, Magnano I, Conti M, et al. Pure post-stroke cerebellar cognitive affective syndrome: a case report. Neurol Sci. 2004;25:220-224. Abstract

43. Levin N, Ben-Hur T, Biran I, Wertman E. Category specific dysnomia after thalamic infarction: a case-control study. Neuropsychologia. 2005;43:1385-1390. Abstract

44. Leathem JM, Martin GT. Cognitive deficits due to asymmetrical bilateral thalamic lesions. Brain Inj. 2001;15:455-462. Abstract

45. Villablanca JR, Marcus RJ. The basal ganglia. A brief review and interpretation. Acta Neurol Latinoam. 1975;21:157-183. Abstract

46. Puce A, Andrewes DG, Berkovic SF, Bladin PF. Visual recognition memory. Neurophysiological evidence for the role of temporal white matter in man. Brain. 1991;114:1647-1666. Abstract

47. Amaral DG. The amygdala, social behavior, and danger detection. Ann N Y Acad Sci. 2003;1000:337-347. Abstract

48. Hunt RD. Functional roles of norepinephrine and dopamine in ADHD. Medscape Psychiatry & Mental Health. 2006;11(1). Available at: Accessed July 28, 2006.

49. Posener JA, Schatzberg AF, Williams GH, et al. Hypothalamic-pituitary-adrenal axis effects on plasma homovanillic acid in man. Biol Psychiatry. 1999;15;45:222-228.

50. Hummel M, Unterwald EM. D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action. J Cell Physiol.


51. Tiihonen J, Kuoppamaki M, Nagren K, et al. Serotonergic modulation of striatal D2 dopamine receptor binding in humans measured with positron emission tomography. Psychopharmacology (Berl). 1996;126:277-280. Abstract

52. Hunt RD, Lau S, Ryu J. Alternative therapies for ADHD. In: Greenhill L, ed. Ritalin: Theory and Practice. New York: Mary Ann Leibert, Inc; 1991:75-95.

Authors and Disclosures

Robert D. Hunt, MD, Center for Attention and Brain Function, Nashville, Tennessee

Disclosure: Robert D. Hunt, MD, has disclosed that he has received grants for clinical research from Lilly, and has served as an advisor or consultant to Shire, Cephalon, Novartis, and Astra-Zeneca.

Medscape Psychiatry & Mental Health. 2006;11(2) © 2006 Medscape