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William C. Nicholson, MSN, PMHNP-BC, Instructor, The University of Alabama at Birmingham-School of Nursing, Room 318, 1701 University Boulevard, University of Alabama at Birmingham (UAB), Birmingham, AL 35249-1210, Office: 205-996-9821, email: chancen@uab.edu
Linda D. Moneyham, PhD, RN, FAAN, Senior Associate Dean for Academic Affairs, Professor, The University of Alabama at Birmingham- School of Nursing, Room 1007, 1701 University Boulevard, University of Alabama at Birmingham (UAB), Birmingham, AL 35294, Office: 205-934-0610, Fax: 205-934-5490, email: moneyham@uab.edu
David E. Vance, PhD, MGS, Associate Professor, The University of Alabama at Birmingham-School of Nursing, Room 2M026, 1701 University Boulevard, University of Alabama at Birmingham (UAB), Birmingham, AL 35294-1210, Office: 205-934-7589, Fax: 205-996-7183, e-mail: devance@uab.edu
Abstract
With the introduction of combination antiretroviral therapy (cART), HIV replication is hindered and gross immune responses are reestablished for many; however, even in the presence of antiretroviral therapy, HIV stimulates constant activation of both the adaptive and innate immune systems which results in a chronic, mild inflammatory state. Despite improved outcomes with cART (e.g., decrease in HIV-associated dementias), adults with HIV continue to exhibit central nervous system mediated cognitive disorders when compared to the HIV negative population. The cognitive disorders, known as HIV-associated neurocognitive disorders (HAND), have been suggested to be related to this chronic, mild inflammatory state. HAND remains quite prevalent, ranging from 52% to 59% of the adult population. These disorders include alterations in executive function, memory, speed of processing, attention, and psychomotor speed.
HIV can infect the brain and impair central nervous system function by influencing endocrine, neuronal, and immune processes. In particular, HIV has been suggested to affect the hypothalamic-pituitary-adrenal axis (HPA-axis), inflammatory response, and microbiome (gut-brain axis) which function concomitantly to regulate physiological function. The interactions of these mechanisms have implications for cognitive function due to their capacity in maintaining systemic homeostasis during physiological stress. Dysfunction in these systems can contribute to the pathogenesis of neurodegeneration when physiological stress becomes chronic. The autonomic nervous system (ANS) regulates a bidirectional interaction between the brain and the gut. The vagus nerve is central to this bi-directional, homeostatic function of the ANS due to its parasympathetic properties and its utilization of afferent and efferent connections.
The vagal nerves convey information between the brain and the gastrointestinal tract forming a neural circuit both in afferent and efferent directions. The efferent vagal nerves regulate gastrointestinal activity, endocrine system, motor function, and mediate inflammatory responses. Vagal afferents transfer information from the gut to the brain (e.g. inflammation) and are suggested as being responsible for behaviors that include lethargy, depression, anxiety, loss of appetite, and sleep disturbances. During stress states, vagal afferent nerves stimulate the HPA-axis which has a primary role in innate immune function by regulating acute stress responses. If the HPA-axis is unable to restore homeostasis (e.g., HIV induced chronic inflammation) over time, it exhausts hormones and neurotransmitters needed for healthy cognitive function. The imbalance in physiological systems leaves the body vulnerable to stress-related effects such as headaches, fatigue, upset stomach, blood pressure and heart rate changes, cognitive impairment, and sleeping problems. In addition, vagal signals from the gut initiate anti-inflammatory responses through afferent signals to the brain which then activate an efferent nerve response. The efferent response activates the cholinergic anti-inflammatory pathway through immune cell interactions which attenuates inflammation through the production of acetylcholine. Acetylcholine has a primary function in cognition and regulating immune responses; however, chronic stress changes how the body utilizes and stores it. The result of these changes could deplete or interfere with the brains ability to store and utilize acetylcholine for cognitive function, therefore, contributing to cognitive disorders.
Chronic inflammatory states can also weaken gut mucosa and epithelial barriers; furthermore, HIV can pervade the gut and alter microbiotic composition into a pathogenic state. Microbiota have been implicated in brain function, homeostasis, immune responses, and digestive processes. Pathogenic microbiota and chronic inflammation could disrupt homeostatic physiological processes and also facilitate the crossing of microbiota into the blood stream through weakened gut barriers (microbial translocation). Microbial translocation is a process when pathogenic material enters the blood stream and threatens the blood-brain barrier by stimulating an inflammatory response. These pathogens induce responses that stimulate subtle brain inflammation which impairs normal cognitive function. The vagus nerve functions to help maintain gut barriers through immune-related processes and its ability to communicate with gut microbiota, but loses this ability in chronic stress states, as is common with HIV (i.e., inflammation).
It is important to note, that stress responses cause the body and brain to utilize essential resources (e.g., nutrients, neurotransmitters, hormones, etc.) for the purposes of survival or removing the threat. If the threat is not removed (e.g., HIV) then the body continues to shunt essential resources to areas specific to the stress response and redirects them from areas unrelated to homeostasis (e.g., select cognitive function). The consequence of this shunting could chronically impair select cognitive functionality due to lack of essential reception and stimulation.
The vagus afferent and efferent connections involve a physiological circuit that is designed to produce a parasympathetic or anti-stress response. On the other hand, HIV promotes a chronic stress state (sympathetic response) which chronically overrides the homeostatic properties of the parasympathetic responses mediated by a functional vagus nerve. Theoretically, HIV could have a pathological effect on the vagus nerve causing dysfunction in its ability to mediate immune responses and signals, thus contributing to the development of cognitive disorders.
In order to explore cognitive interventions in adults with HIV, identifying a pathogenic mediator that coordinates the homeostatic interactions of the neuronal, immune, and endocrine systems would be of interest. It would allow the possibility of more precise targets for treatment which focuses on HIV symptom regulation (i.e., fatigue, upset stomach, cognitive impairments, etc.). Vagus Nerve Stimulation (VNS) is one potential intervention as it targets the vagus nerve and has been utilized as a standard treatment both in clinical depression and epilepsy; furthermore, it has also been utilized in cognitive-based disorders (e.g., Alzheimer’s disease) with mixed results. VNS targets neural plasticity and has the potential to transform current treatment of neurological disorders, but the complexity of physiological interactions that promote plasticity makes it difficult to control. Under normal conditions (homeostasis), plasticity is designed to promote learning through dynamic physiological processes. However, in pathological conditions, the physiological processes driving plasticity are insufficient to restore function (chronic stress). Research has suggested VNS can improve motor speed, psychomotor function, language, and executive functions in patients diagnosed with depression. VNS has also been shown to have a positive effect on memory consolidation, enhancing recognition and recall when utilized in cognitive disorders. Unfortunately, the role of VNS in HIV has not been explored.
The vagus nerve could function as a pathogenic mediator for some HIV symptomology, more specifically cognitive impairment, due to its mediating role in the ANS. Furthermore, VNS has been utilized in adults and is considered to be a safe treatment option for depression, epilepsy, and as an experimental option for Alzheimer’s disease. The benefit in identifying a pathogenic mediator allows for more comprehensive treatment options for adults with HIV as it provides a target for interventions (e.g., pharmaceutical, VNS); furthermore, the potential symptomatic improvement would increase the quality of life for adults who experience HAND.
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