Hypofrontality

Hypofrontality is a state of decreased cerebral blood flow (CBF) in the prefrontal cortex of the brain. Hypofrontality is symptomatic of several neurological medical conditions, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and major depressive disorder.^[1]^[2]^[3] This condition was initially described by Ingvar and Franzén in 1974, through the use of xenon blood flow technique with 32 detectors to image the brains of patients with schizophrenia.^[4] This finding was confirmed in subsequent studies using the improved spatial resolution of positron emission tomography with the fluorodeoxyglucose (18F-FDG) tracer.^[5] Subsequent neuroimaging work has shown that the decreases in prefrontal CBF are localized to the medial, lateral, and orbital portions of the prefrontal cortex.^[6] Hypofrontality is thought to contribute to the negative symptoms of schizophrenia.^[4]^[7]^[8]^[9]

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Flow is technically defined as an optimal state of consciousness. A state of consciousness where we feel our best and we perform our best. It refers to those moments of total absorption when we get so focused on the task at hand that everything else disappears. So our sense of self, our sense of self-consciousness, they vanish. Time dilates which means sometimes it slows down. You get that freeze frame effect familiar to any of you who have seen the matrix or been in a car crash. Sometimes it speeds up and five hours will pass by in like five minutes. And throughout all aspects of performance, mental and physical, go through the roof. Underneath the flow state is a complicated mass of neurobiology. There are fundamental changes in neuroanatomy – which is where in the brain something’s taking place, neurochemistry and neuroelectricity which is the two ways the brain communicates with itself. The most prominent of this is the neuroanatomical changes. So the old idea about ultimate performance flow is what’s known as the ten percent brain myth. The idea that we’re only using ten percent of our brain at any one time so ultimate performance must obviously be the full brain firing on all cylinders. And it turns out we had it exactly backwards. In flow, parts of the brain aren’t becoming more hyperactive, they’re actually slowing down, shutting down. The technical term for this is transient, meaning temporary, hypo frontality. Hypo – H – Y – P – O – it’s the opposite of hyper means to slow down, to shut down, to deactivate. And frontality is the prefrontal cortex, the part of your brain that houses your higher cognitive functions, your sense of morality, your sense of will, your sense of self. All that shuts down so, for example, why does time pass so strangely in flow? Because David Eagleman discovered that time is calculated all over the prefrontal cortex. When parts of it start to wink out we can no longer separate past from present from future and we’re plunged into what researchers call the deep now. Transient hypofrontality is interesting. It was discovered back in the nineties and it had very negative connotations; it was found in schizophrenics and drug addicts. And then in the early two thousands Aaron Dietrich who was then at Georgia Tech discovered or hypothesized that transient hypofrontality actually underpins every altered state – dreaming, meditation, flow, drug addiction – it doesn’t really matter. And then in 2007, 2008 Charles Limb at Johns Hopkins working with first jazz musicians and second with rappers was looking at flow in those contexts and found that the prefrontal cortex was shutting down as well. Though depending on the altered state you get different parts are shut down. Like in flow, one of the most prominent examples is the dorsolateral prefrontal cortex. It shuts down. This is the part of the brain that houses your inner critic, that nagging defeatist always on voice in your head turns off in flow. And as a result we feel this is liberation right. We are finally getting out of our own way. We’re free of ourselves. Creativity goes up. Risk taking goes up and we feel amazing. My mission for the past 15 years has been sort of to reclaim flow research from the hippie community, from the new age community and put it back on a really hard science footing. And really what that took was flow research has been going on continuously at kind of both here and in the United State and Europe all over. And it really just took synthesizing all the information and bringing it together and putting it on a hard and neurobiological footing. That said there’s a bunch left to do, right. We have 150 years of flow psychology and flow science goes back all the way to the 1870s. In fact some of the earliest experiments ever run in kind of early neuroscience and early kind of experimental psychology were run on flow. In the past 25 years as our brain imaging technology has gotten better and better and better we can look farther into the brain and see what’s going on. We’ve got about 25 year of neurobiology that’s underpinning and I sort of think it starts with Dr. Andrew Newberg at the University of Pennsylvania who was looking – he was actually looking at spiritual experiences in meditating Tibetan Buddhists and Franciscan nuns. And he found that “state of cosmic unity” when we become one with everything is actually a byproduct of transient hypofrontality as well. It’s what happens when the hypofrontality moves out of the prefrontal cortex and back into the right parietal lobe which is the part of the brain that separates self from other, right. It allows us to walk through crowded rooms without bumping into people and things along those lines. In flow this portion of the brain shuts down so we can no longer separate self from others. So when people talk about feeling one with everything you’ll get it in action sports – surfers will talk about being one with the waves, mountain climbers one with the mountain, whatever it is. For Buddhists it’s cosmic unity, it’s one with the universe. But what’s really happening is the portion of the brain that separates self from other is shut down so we can no longer distinguish between the two things. And as a result we feel one with everything.

Definition

Hypofrontality is a symptom of numerous neurological diseases defined as reduced utilization of glucose and blood flow in the prefrontal cortex. Hypofrontality can be difficult to detect under resting conditions, but under cognitive challenges, it has been seen to correlate with memory deficits along with executive function deficits. Hypofrontality is also linked to an increase in norepinephrine transmission and decrease in dopaminergic transmission with reduced dopamine efflux in the frontal cortex. ^[10] Others have suggested that 'transient hypofrontality' - brief periods of reduced blood flow to the PFC - are associated with the 'flow' state experienced by professional athletes and musicians, where the explicit command system relaxes, and allows the implicit command system to operate unimpeded.^[11] The transient hypofrontality hypothesis proposes that there is a temporary decrease in the functioning of the prefrontal cortex during high-intensity exercise, specifically affecting tasks such as working memory. This decline is due to the allocation of resources towards movement and the compromise of cognitive functions. The complex mechanisms involved include diverting resources away from cognitive tasks and resulting in a noticeable decrease in prefrontal cortex activity.^[12]

Associated medical conditions

Hypofrontality is known to be a condition associated with the disorders listed below, though the exact role that hypofrontality plays in each of them has yet to be determined. The contribution that hypofrontality has in each case is hard to determine, mostly because the disorders themselves are not fully understood.^[10]

Schizophrenia

Schizophrenia is a mental disorder that most commonly affects social and emotional functioning. Besides emotional and psychological influences, it is believed that genetics and early development play a role in the onset of schizophrenia.^[8] The physical aspects of the disease are actual differences in the brain of the affected. Mostly in the frontal cortex, these differences often stem from a smaller brain volume, and the decreased blood flow that results influences the hypofrontality.^[9] It has not been determined if the reduction of the frontal cortex is the ultimate cause of the symptoms, or if the condition worsens as the symptoms develop.

In addition to all this, schizophrenia is characterized by cognitive impairments in executive function, affecting planning and goal-directed behavior. Negative symptoms are tied to potential dysfunction in the frontal lobe. While neuroimaging studies have yielded inconsistent results regarding brain volume, metabolism, and blood flow, functional neuroimaging during specific tasks demonstrates underactivation of the frontal cortex in schizophrenia. Negative symptoms, referred to as "psychomotor poverty," are linked to decreased frontal activation during tasks, resulting in slowed mental processing and planning deficits. This frontal dysfunction is specific to a sub-syndrome of schizophrenia, with three consistent syndromes: disorganization, positive, and negative. Negative symptoms are associated with compromised long-term adaptation and executive deficits. Tailoring treatment plans to address frontal deficits in real-life situations may enhance the effectiveness of interventions.^[13]

Attention deficit hyperactivity disorder

Attention deficit hyperactive disorder, or ADHD, is most prevalent in children and is considered a developmental disorder. Like the other cognitive conditions that display hypofrontality, ADHD shows decreases in prefrontal cortex size and function.^[7]^{[failed verification]} In ADHD, the underdevelopment is specific to the left side of the prefrontal cortex, as well as the parietal region.

Bipolar disorder

Bipolar disorder is usually expressed through varying mood swings, between high and low. Elevated moods, or mania, are characterized by joy, energy, or irritability. Depressed moods are characterized by pessimism, crying, or lack of confidence. The underlying cause of Bipolar Disorder is not fully understood, but it is believed that abnormalities in the prefrontal cortex may contribute to the lack of emotional control and regulation.^[10]

Major depressive disorder

Major depressive disorder, or MDD, is diagnosed by a persistent low mood that affects the way a person sees themselves and how they live their life. Oftentimes, those with MDD lose interest in what they used to enjoy, are constantly in an edgy mood or display slower movements. MDD and anxiety are commonly expressed comorbidly. Smaller volumes of various brain regions, including the frontal cortex, are common in those who have MDD.^[8]

Mechanism

Hypofrontality is a condition that is symptomatic of many neurological disorders and psychiatric diseases. This suggests that the mechanisms that cause hypofrontality and these neurological conditions are likely to be similar. Hypofrontality likely has pathophysiological mechanisms and neuronal mechanisms. This means that hypofrontality is likely to have causes that stem from bodily changes or changes in neurons. These mechanism names can be combined to be called neurophysiological mechanisms. Currently, the exact neurophysiological mechanisms that cause hypofrontality are unknown. However, there are some possible mechanisms that are plausible and would account for many of the effects of hypofrontality.^[10]

The working explanation of the neurophysiological mechanism behind hypofrontality is that hypofrontality is possibly caused by impaired synaptic connections, which results in diminished neurotransmission. This means that the connections between axons are functioning incorrectly, resulting in the spread of less efficient signals. This proposed explanation could arise from a variety of factors, but it would most likely occur as a result of problems during brain development or genetic factors.^[10]

If hypofrontality is, in fact, caused by these inefficient synaptic connections, then the associated irregular dopaminergic activity in certain parts of the brain (the limbic striatum and mediodorsal thalamus) can be, in part, explained. Dopaminergic activity is the release (or lack thereof) of the neurotransmitter dopamine and the resulting cellular responses. The limbic striatum and mediodorsal thalamus (parts of the brain) have connections with a part of the prefrontal cortex called the corticolimbothalamic circuit. The corticolimbothalamic circuit has a high concentration of GABAergic interneurons, which are neurons that predominantly work with the inhibitory neurotransmitter GABA. As a result of the impaired synaptic connections, the GABAergic interneurons of the corticolimbothalamic circuit would adapt to release increasingly high amounts of GABA to send a signal of the correct strength. This recurrent activation of the GABAergic cells produces a strong inhibitory signal back to the limbic striatum and mediodorsal thalamus, which inhibits the dopaminergic activity in those parts of the brain. This resulting inhibition of dopaminergic activity produces reduced activity at the mRNA and protein level in cells. These cellular changes could call for less blood flow and glucose use specifically, or the less blood flow and glucose metabolism could simply be a result of the lowered cellular activity.^[10]

Diagnostic approach

Since hypofrontality is a condition that alters blood flow and brain glucose metabolism levels, fMRIs or PET scans are used to diagnose hypofrontality. The decrease in blood flow can be best diagnosed with an fMRI, HMPOASPECT, or H2O-PET studies; the decrease in glucose levels can be diagnosed best with 18F-FDG PET imaging studies. These are all different types of imaging studies that use various different chemicals to flag certain molecules, usually glucose.^[14]

Treatment and management

The two main drugs that were thought to potentially be able to reverse hypofrontality and its effects were clozapine and haloperidol; however, neither of the drugs were capable of reversing hypofrontality. Future studies of clozapine showed promise as a treatment in restoring certain aspects of hypofrontality such as the restoration of normal GABAergic neuronal function, but it remained unable to reverse all components of hypofrontality. This suggests that hypofrontality is not caused exclusively by the GABAergic interneurons, and that there is another cause of hypofrontality that is still undiscovered. It is currently thought that a drug that could fully reverse the effects of hypofrontality would also effectively reverse the effects of certain neurological conditions; however, this has not been proven, and the drug has not yet been discovered.^[10] Nevertheless, it has been shown that chronic administration of nicotine reverses hypofrontality in animal models of addiction and schizophrenia.^[15] Moreover, recent studies have shown that the alpha 2 receptor agonists such as clonidine and guanfacine can treat hypofrontality associated with ADHD, PTSD and depression.^[16]^[17]^[18]

Research

Hypofrontality is still not fully understood in its entirety, but there are a number of research projects that have been conducted, leading to progress in recognizing the signs of the symptom. Even though there is still a lot to be learned, experiments on NK1R -/- mice have revealed the role of dopaminergic transmission in hypofrontality. Sagvolden and company conducted a loss-of function mutation where mutant mice lacked the NK1R protein resulting in a low dopaminergic transmission supporting the hypothesis of hypofrontality in ADHD. There has been fewer studies of hypofrontality in depressed patients and drug addiction compared to that of schizophrenia but neuroimaging reports signs of hypofrontality in depressed patients. With hypofrontality being linked to psychiatric diseases, depression, and drug addiction, there is a possibility that they all may have some common pathophysiological mechanism linking the diseases. Even with the large amounts of research on hypofrontality in schizophrenia, there is still a lot to be learned about its neuronal mechanisms. Possible causes are hypothesized to be impaired synaptic connectivity and neurotransmission resulting from neurodevelopmental and/or genetic factors but there is not a complete understanding hypofrontality as a whole.^[19]

Current research is also being done in mice to try to replicate the conditions that occur in patients with hypofrontality to determine how it is caused and how it might be fixed.^[10]

References

^ Bullmore, E.; Brammer, M.; Williams, S. C. R.; Curtis, V.; McGuire, P.; Morris, R.; Murray, R.; Sharma, T. (1999). "Functional MR imaging of confounded hypofrontality". Human Brain Mapping. 8 (2–3): 86–91. doi:10.1002/(SICI)1097-0193(1999)8:2/3<86::AID-HBM3>3.0.CO;2-S. PMC 6873309. PMID 10524597.
^ Rubia, K.; Overmeyer, S.; Taylor, E.; Brammer, M.; Williams, S. C.; Simmons, A.; Bullmore, E. T. (1999). "Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: A study with functional MRI". The American Journal of Psychiatry. 156 (6): 891–896. doi:10.1176/ajp.156.6.891. PMID 10360128.
^ Molina, V.; Sanz, J.; Reig, S.; Martínez, R.; Sarramea, F.; Luque, R.; Benito, C.; Gispert, J. D.; Pascau, J.; Desco, M. (2005). "Hypofrontality in men with first-episode psychosis". The British Journal of Psychiatry. 186 (3): 203–208. doi:10.1192/bjp.186.3.203. PMID 15738500.
^ ^a ^b Ingvar, D. H.; Franzén, G. (1974). "Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia". Acta Psychiatrica Scandinavica. 50 (4): 425–462. doi:10.1111/j.1600-0447.1974.tb09707.x. PMID 4423855. S2CID 20635668.
^ Buchsbaum, Monte S. (1982). "Cerebral Glucography With Positron Tomography". Archives of General Psychiatry. 39 (3): 251–9. doi:10.1001/archpsyc.1982.04290030001001. ISSN 0003-990X. PMID 6978119.
^ Andreasen, N. C.; O'Leary, D. S.; Flaum, M.; Nopoulos, P.; Watkins, G. L.; Boles Ponto, L. L.; Hichwa, R. D. (1997). "Hypofrontality in schizophrenia: Distributed dysfunctional circuits in neuroleptic-naïve patients". Lancet. 349 (9067): 1730–1734. doi:10.1016/S0140-6736(96)08258-X. PMID 9193383. S2CID 6394583.
^ ^a ^b Liddle, P. F.; Friston, K. J.; Frith, C. D.; Hirsch, S. R.; Jones, T.; Frackowiak, R. S. (1992). "Patterns of cerebral blood flow in schizophrenia". The British Journal of Psychiatry. 160 (2): 179–186. doi:10.1192/bjp.160.2.179. PMID 1540757. S2CID 44779908.
^ ^a ^b ^c Andreasen, N. C.; Rezai, K.; Alliger, R.; Swayze II, V.W.; Flaum, M.; Kirchner, P.; Cohen, G.; O'Leary, D. S. (1992). "Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London". Archives of General Psychiatry. 49 (12): 943–958. doi:10.1001/archpsyc.1992.01820120031006. PMID 1360199.
^ ^a ^b Weinberger, D. R. (1987). "Implications of normal brain development for the pathogenesis of schizophrenia". Archives of General Psychiatry. 44 (7): 660–669. doi:10.1001/archpsyc.1987.01800190080012. PMID 3606332.
^ ^a ^b ^c ^d ^e ^f ^g ^h Pratt, J. A., C. Winchester, A. Egerton, S. M. Cochran, and B. J. Morris. "Modelling Prefrontal Cortex Deficits in Schizophrenia: Implications for Treatment." British Journal of Pharmacology 153.S1 (2008): S465-470. Web. 23 Feb. 2015.
^ Dietrich, A. (2004). "Neurocognitive mechanisms underlying the experience of flow". Consciousness and Cognition. 13 (4): 746–761. doi:10.1016/j.concog.2004.07.002. PMID 15522630. S2CID 16361796.
^ Jung, Myungjin; Ryu, Seungho; Kang, Minsoo; Javadi, Amir-Homayoun; Loprinzi, Paul (Jul 2022). "Evaluation of the transient hypofrontality theory in the context of exercise: A systematic review with meta-analysis". Q J Exp Psychol (Hove). 75 (7): 1193–1214. doi:10.1177/17470218211048807. PMID 34523365.
^ Semkovska, M; Bédard, MA; Stip, E (Sep–Oct 2001). "Hypofrontality and negative symptoms in schizophrenia: synthesis of anatomic and neuropsychological knowledge and ecological perspectives". L'encephale. 27 (5): 405–415. PMID 11760690.
^ Liemburg, E. (2012). "Antipsychotic medication and prefrontal cortex activation: A review of neuroimaging findings". European Neuropsychopharmacology. 22 (6): 387–400. doi:10.1016/j.euroneuro.2011.12.008. PMID 22300864. S2CID 24877454.
^ Koukouli F.; Rooy M.; Tziotis D.; Sailor K. A.; O'Neill H. C.; Levenga J.; et al. (2017). "Nicotine reverses hypofrontality in animal models of addiction and schizophrenia". Nat Med. 23 (3): 347–354. doi:10.1038/nm.4274. PMC 5819879. PMID 28112735.
^ Arnsten, A.; Connor, D. (2015). "The effects of stress exposure on prefrontal cortex: Translating basic research into successful treatments for post-traumatic stress disorder". Neurobiology of Stress. 1: 89–99. doi:10.1016/j.ynstr.2014.10.002. PMC 4244027. PMID 25436222.
^ Fu, C.; Reed, L. (2001). "Noradrenergic dysfunction in the prefrontal cortex in depression: an [15O] H2O PET study of the neuromodulatory effects of clonidine". Biol Psychiatry. 49 (4): 317–325. doi:10.1016/s0006-3223(00)01050-7. PMID 11239902. S2CID 33493332.
^ Arnsten, A. (2009). "The Emerging Neurobiology of Attention Deficit Hyperactivity Disorder: The Key Role of the Prefrontal Association Cortex". J Pediatr. 154 (5): I-S43. doi:10.1016/j.jpeds.2009.01.018. PMC 2894421. PMID 20596295.
^ Yan, Ting C.; Hunt, Stephen P.; Stanford, S. Clare (2009). "Behavioural and Neurochemical Abnormalities in Mice Lacking Functional Tachykinin-1 (NK1) Receptors: A Model of Attention Deficit Hyperactivity Disorder". Neuropharmacology. 57 (7–8): 627–635. doi:10.1016/j.neuropharm.2009.08.021. PMID 19748515. S2CID 17031647.

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