COMMENTARY

The Neurobiology of ADHD

Robert D. Hunt, MD

Disclosures

September 25, 2006

In This Article

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 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).

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