ADHD: Attention deficit or Hyper-attentive?!

Introduction:

ADHD (Attention Deficit Hyperactive Disorder) as the most hereditary disorder of humans, physical or psychological/behavioural has been perhaps the most recognized truly in the field of medicine, even among the experts and researchers. This common disorder starting in childhood, but if untreated endures across the life span, has been known in different terms from the time of antiquity. Hippocrates (460-329 BC) (1), known as the father of medicine, observed patients who demonstrated “quickened responses to sensory experiences” and went on to describe their inability to stay focused “because the soul moves on quickly to the next impression.” Interestingly this ancient Greek physician recognized the condition both as a cognitive and behavioral nature together and not separate. But it took the field about two millennia to bounce back and forth, between recognizing it as predominantly a motoric (hyperactive) condition to a cognitive (inattentive) disorder until the present day. 

George Frederick Still (2), the father of British Pediatrics, in 1902 described and published in the Lancet, the descriptions of 43 children with serious problems of sustained attention and self-regulation, but at the same time paradoxically being “bright and intelligent”. Dr. Still was perhaps the first one to recognize the problem with “self regulation” instead of the label of “Moral Defect” on these children up until 20th century and also appreciating their high intelligence, that has not been widely acknowledged even today! In contrast with the positive and intelligent observation of Still, for the rest of 20th century and even now in 21st century, these children have been mislabeled negatively with having “mild brain damage”, “minimal brain dysfunction”, “mental deficiency”, etc. (e.g. 3-4)

The pathophysiologic or causative theory of ADHD prompted by Charles Bradley (1902-1979) in 1937, a pediatric neurologist who by accident treated these children Benzedrine sulfate, an amphetamine product with great success, so to born the theory of “dopamine deficiency” prominent to this day. (5-6) In 1952, first edition of DSM (Diagnostics and Statistical Manual) of psychiatric disorders by the APA (American Psychiatric Association) (7) did not include any mention of an ADHD like disorder. Then in 1957, after Laufer and colleagues (8), reporting inattention and hyperactivity, both as two main features of the condition, the second edition of DSM in 1968, included the disorder as a formal diagnostic classification. (9) But before that another bright physician, Keith Conners in 1963 started his first study on the effects of Ritalin (Methylphenidate) in ADHD children and a year later published the first “Conner’s Rating Scale” for the official assessment and rating of the ADHD that is still in common use today. (10)

In recent years first DSM-IV in 1994 (11) and most recently DSM5 in 2013 (12), have classified the disorder into two subtypes of predominantly inattentive (ADHD-I) and predominantly hyperactive/impulsivity (ADHD-HI), though these they often overlap at least in research samples as “combined”! Impulsivity as a very cardinal feature of ADHD that has been recognized only in recent decades in the disorder, has been poorly defined in DSM-IV & 5 as only “ blurting out” verbally, or “having trouble waiting one’s turn”, and “interrupting or intrudes on others” again more verbally. And the only change from DSM-IV to DSM 5 after a quarter of century has been extending the age of onset from 7 to 12, so prompting some to propose wrongly the new entity of adult onset ADHD. (13)

 In this article that is a synopsis of my initial work (“ADHD: Revisited” and “ADHD: Hyperattentive, disinhibited, intelligent and evolutionary”) (14-15) I will dissecting into the true nature of ADHD, and reveal its misconceptions, misunderstandings, the shortcomings in its research and its current wrong classification and treatment.

Two young girls having fun painting everything. Childhood, learning, exploration family

 ADHD: One type or subtypes?

On a descriptive level, the symptomatology of two distinct ADHD subtypes of hyperactive-impulsive (ADHD-HI) and inattentive (ADHD-I) are quite different and hardly seem to come under the same disease entity as it has long been categorized by DSM classifications with no change in the recent DSM5. (12) Phenomenologically if the pure inattentive subtype without any hyperactivity and impulsivity exists, that will be only an “attention-deficit” disorder or ADD. (14-15) As a result, the majority of research samples, hence the conclusions of the literature for clinical practice have relied heavily on the “combined subtype”. Unfortunately the combined subtype that is ill defined and usually is not consisted of 6 symptoms of either subtypes as required by DSM5, but some of the symptoms of each, is a mixed and arbitrary construct that if either subtypes would be different disease entities, will mix up not only the phenotypes but all the underlying pathophysiology. That is why the literature and research have been so inconclusive over ADHD in all aspects. This contradicting fact has long caused an intense argument in the literature on the total validity of ADHD as a homogenous or single disorder with a single pathophysiology or two or more heterogeneous disorders with different pathophysiology (16-17) that I will attempt to review and explore further here.

 Unfortunately there are not many comparison studies between the two subtypes in the literature, but a few existing have shown that there is a distinct difference between the two with the conclusion that ADHD is a heterogeneous condition with differences not only in symptomatology and the course of illnesses across the brain development, but differences in cognitive functions and different etiopathophysiology.(18-25) Goth-Owens et al. (20) in their comparison study of 572 children and adolescents with pure inattentive subtype (ADD), combined type (ADHD-C) and non-ADHD controls, reported slower cognitive interference speed in the ADD vs. ADHD-C and controls comparisons. A similar result has been reported by Solanto et al. (21 ) that predominantly inattentive subtype show worse performance than combined subtype and control groups on the WISC-III Processing Speed Index. This has made some researchers to question the validity of DSM current diagnostic criteria of ADHD to include two distinct subtypes of inattentive and hyperactive/impulsive under the same diagnostic umbrella. (22) Martel et al. (23) in comparison between the two subtypes, reported “a composite executive function factor was significantly related to inattentive but not hyperactive-impulsive symptoms.” The authors concluded “Executive function weakness in adolescent ADHD is specifically related to symptoms of inattention-disorganization.” Nigg et al. (24) also reported that symptoms of inattention-disorganization were uniquely related to executive functioning when hyperactivity-impulsivity controlled. “Inattention was associated with slower response speed, and hyperactivity-impulsivity with faster output speed. Results were not accounted for by IQ, age, gender, education level, or comorbid disorders.” Also Marshal et al. (25) found academic underachievement in a group of 6-12 years old with ADHD without hyperactivity.

The extension and probably progression of the cognitive deficit and poor academic performance across life span in the inattentive subtype is in contrast with the improvement of cognition and even some of the behavioral profiles in the hyperactive-impulsive subtype. In a meta-analytic review of 86 studies of children and adolescents (N = 163,688) and 11 studies of adults (N = 14,112), by Wilcutt (26) the subtype symptoms group change, with a significant improvement in ADHD-HI but not ADHD-I. The prevalence of the hyperactive/impulsive subtype declines from 4.9% in 2-3 years old down to 2.9% in 6-12 years old, down to 1.1% in adolescence and remains the same in adults. But in sharp contrast, the prevalence of ADHD-I rises from 2.2% in preschoolers to 5.1% in 6-12 years old and slightly up to 5.7% in adolescents with a decline in adulthood to 2.4%. While in the analysis and report of Wilcutt (26), it seems that the prevalence of ADHD-I is lowering when reaching adult age, more detailed analysis of the adult studies (available in the supplement table 10 of Wilcutt’s report) reveals that majority of study samples show a prevalence of >4% for ADHD-I compared to 1.6% in the ADHD-HI in adulthood. The reason for of lowering the final prevalence number in analysis has been that some studies sample such as Kessler et al. (27) has had no subtype comparison.

 From a few available studies comparing the cognitive functions of the two subtypes, differences in this cardinal feature of the disorder have been observed. Wåhlstedt et al. (28) found among four neurocognitive variables (inhibition, working memory, RT variability, delay aversion), only inhibition and RT(Reaction Time) variability “specifically related to symptoms of inattention” and “none of the neuropsychological measures was primarily related to symptoms of hyperactivity/impulsivity” and ADHD-HI performed superiorly in several measures of executive function. Although ADHD-HI subjects could have deficits in “sustain attention” and get bored easily and fail on such tasks as in the classroom settings, their attentions seem to be selective and they perform better on fast-paced than slow-paced tasks, with the abilities to perform multi-tasking by dividing and switching their attentions between interested tasks. (29) This could explain why some researchers have already questioned the validity of ADHD-HI in the presence of high IQ to be mixed with ADHD-I and combined subtypes and reaching the mixing conclusion of the association of the condition with learning disabilities and impairment in executive functions. (30-32)

 At the underlying neuropathological level, the difference between the two subtypes has also been shown. Sagvolden et al. (33) in their “ dynamic developmental theory” have differentiated between the two ADHD subtypes by linking “ hypofunctioning mesolimbic and nigrostriatal dopamine” to hyperactivity/ impulsivity subtype and “hypofunctioning mesocortical dopamine” to inattentive subtype. These authors hypothesize that a hypofunctioning mesolimbic dopamine branch produces altered reinforcement of behavior and deficient extinction of previously reinforced behavior. This gives rise to delay aversion, development of hyperactivity in novel situations, impulsiveness, deficient sustained attention, increased behavioral variability, and failure to “inhibit” responses (“disinhibition”). A hypofunctioning mesocortical dopamine branch will cause attention response deficiencies (deficient orienting responses, impaired saccadic eye movements, and poorer attention responses toward a target) and poor behavioral planning (poor executive functions). A hypofunctioning nigrostriatal dopamine branch will cause impaired modulation of motor functions and deficient non-declarative habit learning and memory. This theory somewhat is in agreement with a long-theorized response or behavioural disinhibition as the core pathophysiological process in ADHD of hyperactive-impulsive subtype.

 Also at a neurogenetic level, Eisenberg et al. (34) in their pilot study on the genetic risk study of ADHD in 1999 showed “ the impulsive-hyperactive type of ADHD (excluding inattention) was associated with the high enzyme activity COMT val allele.” COMT (Catechol-O-methyltransferase) is the enzyme that degrades dopamine in the prefrontal cortex with its val allele degrades dopamine faster (four times) than its met allele and has been shown to be more abundant in ADHD-HI than even the normal brains. The Val allele of COMT gene is an evolutionary polymorphism, resulting in a substitution of methionine (Met) for valine (Val) in the COMT enzyme. (35) In the human brain, Met/Met homozygotes having about 40% less COMT activity than Val/Val homozygotes in the prefrontal cortex. (36) The alleles are co-dominant, resulting in Val/Met heterozygotes having an intermediate level of COMT activity. (37) This evidence strongly suggests that Met/Met homozygotes have the highest baseline level of dopamine available in the prefrontal cortex (because dopamine is four times less consumed) with Val/Met heterozygotes having an intermediate level and Val/Val homozygotes having the lowest level of prefrontal dopamine, as a result of high consumption. (38) All these neurobiological facts reveal that in fact the “dopamine deficiency” theory of ADHD-HI is wrong and should be replaced by the “dopamine insufficiency” theory. (14-15)

Also Cao et al. (39) using diffusion magnetic resonance imaging and probabilistic tractography method to examine whole-brain white matter (WM) in ADHD subjects have showed that decreased structural connectivity in the prefrontal-dominant circuitry is correlated with the “inattention”, but increased connectivity in the orbitofrontal-striatal circuitry, with the “hyperactivity/impulsivity” symptoms. There is also an age-related relationship in the availability of striatal dopamine transporter (DAT) that transports dopamine across the brain specifically to the frontal and prefrontal areas. This availability has been shown to be quite higher in ADHD-HI and not in the inattentive subtype. Also by age the availability is lowered, so that there is lower DAT density in adults with ADHD, in contrast with children with ADHD. This has a clinical significance in the treatment of ADHD across life span that means the dose of stimulants need to lower as the age increases, as in the adult age the density of DAT to transport the increased dopamine caused by the stimulants decreases by age. Lack of attention to this fact would lead to more side-effects with stimulants in the adults as mentioned earlier. (40-43)

Also the increase in the val allele of COMT across life span is consistent with the brain development, meaning that ADHD-HI is a developing brain condition than a neurodevelopmental disorder that could be the case with the inattention subtype or ADD. (14-15, 29, 44) The dopamine transporter DRD4 gene, specifically the variant “7-repeat allele” has also been strongly associated with cADHD (childhood onset ADHD) that persists to adulthood (45), opposed to other gene variants of DAT1 9 & 10 repeat alleles that have been associated with poor response to stimulants and perhaps mostly associated with the inattention subtype. (46-48) This fact is also in contrary to the recent suggestions by some researchers (49) that ADHD could have an onset even in adulthood and the adult ADHD may not be a continuum of childhood onset ADHD.

In summary, the hyperactive impulsive subtype of ADHD seems to be the only true ADHD in need and with positive response to stimulant medications, for provision of a hyperactive and intelligent brain of dopamine insufficiency with more dopamine.

 An Attention Disorder that its attention was never explored:

ADHD that its main deficit or pathology is nowadays considered to be in attention, never was explained or studied for attention. The whole DSM5, the psychiatric bible that classifies mental disorders, including ADHD and is followed by everyone in clinical practice and research, never mentions of what type of attention, this disorder has deficit in. Despite the wrong assumption of DSM and others in the field of ADHD that attention is only one type that is defective in this disorder, the cognitive science classifies attention into four types: 1.Sustained, 2. Selective, 3. Alternating or Switching, and 4. Divided. (50-54)

 In ADHD only the first type of attention, that is sustained attention is in deficit. What is sustained attention? That is an attention that requires a continuous mental or cognitive response, reception or effort of the subject towards the stimulus, activity or task. (51) ADHD subjects due to their hyperactivity and easily boredom with continuous and boring tasks or activities that are not interesting to them, are not able to sustain their attention for long to such tasks, such as in the classrooms. But these subjects in fact perform better on the other three types of attention, i.e. selective, alternating/switching and divided attentions. First of all ADHD of hyperactive/impulsive subtype possess a selective attention, meaning that they are interested in tasks that interest them, so they stay focused on and excel, such as math, science, computer games or fast not slow boring tasks such as usual classroom settings and subjects. These subjects are also generally good in alternate or switch and divide their attentions between different tasks if interest them, so capable of multi-tasking, better than so called “normal” peers. All these types of attentions, specially the selective, alternating/switching and divided attentions, particularly in our era of fast-paced and multi-tasking world are pre-requisites of high intelligence. (53-54) In fact the sustained attention is more under the control of cholinergic cortical neurotransmission and frontal and parietal cortices than the other types of attention that are more under coordination of dopamine and norepinephrine and all cortical regions. (50) Moreover as I will explore and discuss more later on, while sustained attention is related to a general intelligence that all current IQ tests measure, the other types of attention that I have coined them together as “dynamic attentions” (14-15) are related to a high and specialized intelligence that is hard to measure with the current IQ tests or any if at all!

 Beyond impulsivity: Behavioral Disinhibition in ADHD:

ADHD contains more than impulsivity that DSM5 has defined as blurting, butting into conversation or intruding into others. ADHD subjects are in general disinhibited or in a better word, out of control or as George Still explained it first in 1902, has a self-regulation deficit. (2) Later on other researchers such as Pontius (55), Mattes (56), Chelune and colleagues (57), Shue and Douglas (58) from early 1970’s to early 1990’s noticed similarities between disinhibition of ADHD and frontal lobe type of disinhibition that is more of a general behavioral type. But later on from late 1990’s onward until now, this behavioral disinhibition has been either narrow visioned to the cognitive domain and defined as difficulty in “response inhibition” (59-62) or totally ignored and like DSM5 sufficed with noticing impulsivity in the afflicted subjects alone.                 

Although long time ago, first Still, then others such as Quay (62) observed and expanded impulsivity in ADHD as “impulse control” with symptomatic presentations such as immediate reinforcement seeking and poor impulse control, this keen observation did not go far enough to appreciate this disorder in its true self to cover a general behavioural disinhibition that I explored farther for the first time. (14-15) although Barkley in modern era (59) proposed behavioural inhibition defect as the center core of the condition, he did not go beyond cognitive and executive dysfunctions. This lack of recognition of a general behavioural disinhibition in ADHD as a core feature of the illness, is despite numerous studies of the its direct link with conduct and oppositional defiant disorders, other delinquencies, substance use and other risk taking behaviours such as impatience in driving and road rages in this patient population. (29-74) 

Unfortunately the field has over-emphasized on comorbidities of ADHD such as mood disorders and learning disabilities and has included all the above complications or manifestations of behavioural disinhibition as such, instead of “post-morbidities” that was coined by me for the first itme. (14-15) By definition comorbidities are more than one condition when coexist at the same time with the same time of onset. But if a primary condition such as ADHD existing from early childhood, later on leads to other complications such as mood disorders, learning disabilities, the term “post-morbidities” would be more appropriate as it provides a causal link between the conditions. This kind of distinction also guides a better treatment plan, as it would be more wise to treat the primary condition that could improve the secondary condition(s). 

Reward and Novelty Seeking:

Linked and closely tied to behavioural disinhibition are two other relatively main cardinal features of ADHD, the reward and novelty seeking. These two behavioural characteristics of ADHD, have been repeatedly shown and proven in animal and human studies to be also associated with the dopamine function and the pathology of cortico-striatal anatomic pathway in this disorder. (75-81) ADHD subjects unlike others such as peers, bored of ordinary and usual things are seeking rewards and novelties. That is why if not treated early, they are at the risk of seeking monetary or pleasure rewards by getting into illicit drugs, gambling and internet gaming. Their novelty seeking pushes them to jumping from one thing, one relationship, or one career to another, so appear them as very unstable individuals. (69-71, 82-84) At the same time, these features are evolutionary and necessary in the modern humans for achievements, inventions, productivity, creativity and success. In fact novelty-seeking dopamine receptor DRD4 polymorphisms are associated with human migration out-of-Africa, even after controlling for neutral population gene structure. (85) This polymorphisms associated with increased exploratory behavior, novelty seeking, and risk taking, collectively considered as novelty-seeking trait, has been widely observed in ADHD-Hyperactive/Impulsive (ADHD-HI) subtype. (86-93) 

A Dynamic, hyperattentive and intelligent brain:

As partly discussed earlier, the brain of ADHD-HI is deficient in sustained attention due to its other modes of attention, i.e. dynamic attention. A brain with “dynamic attention” that I have coined (14-15) collectively for selective, switching/alternating and divided attentions, cannot sustain its attention on one task for long, unless the task is selectively interesting. This evolutionary feature of human with its specific dopamine receptor DRD4 polymorphism, as discussed above, has been a pre-requisite for productivity, creativity and invention that have made the modern human. Therefore as I will show in the following, this hyper-attentive brain that ADHD-HI is a very robust example of that, is very intelligent, not in a sedentary, slow-paced manner, but dynamic and fast-paced rhythm that fits well with the modern life. Our human brain did not stop evolving since human evolved from apes, but continues with its evolution in very settle ways. The evolution has made our brains more and more intelligent, flexible and dynamic over time, capable of coping, creating, and more and in the modern digital era capable of multi-tasking and fast and accurate reacting to the demands of the environment. 

It has been shown that both selective and alternating/switching attentions require intelligence and are developmental, fundamental to almost all cognitive tasks, associated with cognitive flexibility that is related directly to the brain plasticity. (51, 53, 94) These dynamic attentions and cognitive flexibility, requiring the brain plasticity and coordination of different anatomical structures of the brain form the top (prefrontal cortex, cingulate cortex and parietal areas) to the bottom (striatum) and more have been substantiated. (95-96) This is unfortunately in contrast with the ADHD literature at large that shouting loud that ADHD subjects have impairment in their cognitive functions through difficulties in their executive function and working memory tests. But as alluded earlier, all these tests including the commonly used IQ tests of Wechsler’s are all based on “sustained attention” and not “dynamic attentions”! (e.g. 97) 

It has also been shown that the genotype of Val/Val vs. Met /Met or Met/Val of COMT (Catechol-O-Methyl-Transferase), the main degrading enzyme of dopamine is linked to higher plasticity. (98) Moreover a more intelligent and plastic brain as human has evolved, uses more “neural efficiency” specially of the cerebral cortex, and in a better word, higher intelligence more efficiently utilizes all the neurons, their connections, synapses and their neurotransmission contents. All these seem to be more compatible with the brain of ADHD-HI. (99-103) It has also been shown that ADHD subjects with above median IQ have stable cortical development of the brain, whereas ADHD with below median IQ, that is probably the inattentive subtype is associated more with a delay of cortical development. (31) Moreover intelligence comes in different forms and as different talents and skills that the current IQ tests are lacking the power of such precise measurement. For example, a research group from China in a sample of boys with ADHD have shown that there is a difference between performance IQ, verbal IQ and full scale IQ measured by Wechsler IQ test. These researchers have shown that the Val158Met polymorphism of COMT enzyme, and the monoamine oxidase A (MAOA) gene containing a VNTR polymorphism (MAOA-uVNTR), both contributing to the enzymatic degradation of dopamine and noradrenaline in the prefrontal cortex and influencing cognitive abilities, including intelligence. The authors reported that the COMT x MAOA interaction after adjustment was the only factor significantly predicted the performance IQ scores that seems to be higher in ADHD-HI than verbal IQ. (105)

ADHD: An Evolutionary Brain Condition:

ADHD as the most hereditary human condition (77-82% among twins) in comparison with cancers and autoimmune disorders that rarely exceeds 30% must be evolutionary. The prevalence of ADHD is also increasing over time, from as low as 1-3% in the past up to about 16% of some recent statistics. (106-107) As we know since Darwin, evolution is adaptive (108-109), and novelty-seeking DRD4 polymorphisms have been found to be associated with early humans migration around the globe. (85) This DRD4 polymorphism and its more evolutionary 7R allele has been found at a higher frequency in ADHD-HI associated genetic variant (7R alleles) (110). Therefore ADHD has been proposed as being an evolutionary adaptive condition. (14-15, 111-113) Also as discussed here and elsewhere (14-15) and by others (111-113), dynamic attentions, immediate and fast response and excellence in fast-paced tasks, and multi-tasking are all the outcome of an evolutionary adaptation that ADHD-HI is a robust example.      

 Moreover evolution is not only inter-species, but also intra-species or happening among the same species including us. This intra-species evolutionary differences or variations have already been shown in mosquitos in their competence (114), in evolution of the yeasts (115), bacteria (116) and more recently in the human brains. The intra-species polymorphism such as the ones in our brain genetics have evolved through interaction and adaptation with the environment as the different variety of polymorphism in dopamine degrading enzymes such as MAO, COMT and DRD’s have occurred. These genetic polymorphisms are the underpinning of our brain plasticity and lack or defect in them are causes of many brain disorders or at the best an average intelligent and plastic brain.(117-123)

 Conclusion: ADHD or HAADD?!

As detailed, argued and proposed elsewhere (14-15), ADHD of hyperactivity/impulsive subtype that seems to be the only true ADHD, while may have deficit in sustain attention, they are hyperattentive in dynamic attentions (selective, switching and divided) so capable of multi-tasking and fast-paced tasks. I have shown succinctly here that the brain of ADHD-HI is in fact hyper-attentive, intelligent, developmental and evolutionary. Such a brain has been evolved and drifted fast and growing in prevalence compared to the average brain that is more static and fit for sustain attention and tasks that perceived as boring by a dynamic, hyperattentive and evolutionary brain. Therefore I have proposed the change of the label of the condition from ADHD to HADD (Hyperactive-Attentive-Disinhibitory Disorder). (14-15) HAADD is not a neuro-developmental delay disorder such as inattentive subtype or ADD, but a developing brain condition. This evolutionary condition of the brain has surpassed the nature so in insufficient in dopamine so in need of stimulant medications to avail enough of this neurotransmitter for optimal development and function. In the far future there is the possibility that the nature provides sufficient dopamine to this brain so it will not be in the need of this chemical. The last word, it is possible that such kind of brain already exists with sufficiency of dopamine and all positive, developed and evolutionary features of HAADD, without hyperactivity or behavioural disinhibition, or in a better word, a super-intelligent, hyperattentive, thinker and creative brain!

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