Researchers at the University of Colorado Anschutz Medical Campus have shown a direct link between vagus nerve stimulation and its connection to the learning centers of the brain. The discovery may lead to treatments that will improve cognitive retention in both healthy and injured nervous systems.
The study was published last week in the journal Neuron.
“We concluded that there is a direct connection between the vagus nerve, the cholinergic system that regulates certain aspects of brain function, and motor cortex neurons that are essential in learning new skills,” said Cristin Welle, PhD, senior author of the paper and the vice chair of research for the Department of Neurosurgery at the University of Colorado School of Medicine.
Researchers taught healthy mice a task that’s normally difficult to see if it could help improve learning. They discovered that stimulating the vagus nerve during the process helped them learn the task much faster and achieve a higher performance level. This showed that vagus nerve stimulation can increase learning in a healthy nervous system.
The study also revealed a direct connection between the vagus nerve and the cholinergic system that’s essential for learning and attention. Each time the vagus nerve was stimulated, researchers could observe the neurons that control learning activated within the cholinergic system.
Damage to this system has been linked to Alzheimer’s disease, Parkinson’s disease and other motor and cognitive conditions. Now that this connection has been established in healthy nervous systems, Welle said it could lead to better treatment options for those whose systems have been damaged.
“The idea of being able to move the brain into a state where it’s able to learn new things is important for any disorders that have motor or cognitive impairments,” she said.
“Our hope is that vagus nerve stimulation can be paired with ongoing rehabilitation in disorders for patients who are recovering from a stroke, traumatic brain injury, PTSD or a number of other conditions.”
In addition to the study, Welle and her team have applied for a grant that would allow them to use a non-invasive device to stimulate the vagus nerve to treat patients with multiple sclerosis who have developed movement deficits. She’s also hoping this device could eventually help healthy people learn new skills faster.
“I think there’s a huge untapped potential for using vagus nerve stimulation to help the brain heal itself,” she said. “By continuing to investigate it, we can ultimately optimize patient recovery and open new doors for learning.”
Locus Coeruleus Modulation of Neural and Glial Cells Following Vagus Stimulation
Vagus nerve efferents target a wide range of organs including the heart, lungs, gastrointestinal system, many glands and smooth muscle. However, the majority (∼80%) of vagal nerve fibres are afferent. A large proportion of these sensory fibres converge onto the spinal trigeminal nuclei of the medulla and the nucleus of the solitary tract (NTS). A monosynaptic projection from the NTS regulates the activity of the locus coeruleus (LC) which provides the sole source of norepinephrine (NE) within the brain (Janitzky, 2020) (Figure 1).
Vagal nerve stimulation (VNS) leads to a stimulation-intensity dependent increase in extracellular concentrations of NE in the hippocampus and cerebral cortex of rats, released from the LC (Roosevelt et al., 2006; Shen et al., 2012). Unmyelinated projections of the LC can communicate monosynaptically or by volume transmission, whereby neurotransmitters are released from varicosities along the axon that do not make contact with other synapses. At these varicosities NE diffuses into the surrounding space where it may act on neurons and glial cells (Feinstein et al., 2016). LC firing generates tonic or phasic release of NE; tonic firing is related to states of sleep and wakefulness, with a frequency of 1–3 Hz whilst awake (Howells et al., 2012), and helps to gate environmental inputs, while phasic firing occurs on encountering sensory inputs and during tasks that require attention, such as investigating a novel object.
In advanced AD, there is an evident degeneration of LC neurons (Bondareff et al., 1981). It has been proposed that early damage to the LC in the preclinical phase of AD may result in abnormally high tonic activity of the LC (Elman et al., 2017) which can impair phasic LC discharge, and that vagal stimulation may provide an avenue to restore phasic LC firing as suggested from research in rats (Janitzky, 2020).
Vagus Nerve Stimulation
Vagal nerve stimulation (VNS) is currently used to treat refractory epilepsy that does not respond to pharmaceutical interventions in patients unsuitable for resective surgery, and for treatment-resistant depression. The first surgically implanted (i) VNS device was approved by the FDA (1997) to reduce the frequency, severity and length of seizures. iVNS devices are implanted in the chest under the clavicle, and cuff wires wrapped around the cervical vagus nerve trunk provide direct stimulation.
Technology for other neuromodulation devices has moved faster than VNS; clinically approved devices for epilepsy include the brain-responsive neurostimulation (RNS) system which can deliver fine-tuned electrical stimulation in response to specific epileptiform activity (Jarosiewicz and Morrell, 2021), and two closed-loop devices have been FDA-approved for deep brain stimulation, and one for spinal cord stimulation (Fleming et al., 2020).
Although well tolerated, invasive VNS implantation and management can have side effects in approximately 10–30% of patients (Morris and Mueller, 1999). Surgical complications have been reported to occur in 9–17% of patients (Kahlow and Olivecrona, 2013; Révész et al., 2016) and these include hematoma, superficial or deep infection, and vocal cord palsy. Post-implantation issues after one year include hoarseness, paraesthesias, headache and shortness of breath.
In addition to biological effects there is the risk of technical issues reported in 4–17% of patients (Kahlow and Olivecrona, 2013; Révész et al., 2016) such as lead fracture, disconnection, spontaneous turn-off, stimulator malfunction, battery or electrode failure and lead breakage, which require repeat surgery to correct. These complications have hampered the development of VNS use into patient groups outside epilepsy and depression as they imply further cost and readmissions.
To circumvent complication rate with iVNS, non-invasive devices have been developed and are currently being tested in clinical trials. However, clinical information on iVNS performance in the context of randomised control trials would be helpful to directly compare it with less or more invasive procedures (transcutaneous VNS or DBS, respectively) and weigh the risks against the benefits it could afford.
Transcutaneous VNS (tVNS) can be applied through locations on the ear (auricular) or in the neck (cervical) (Yap et al., 2020). There is functional MRI (fMRI) evidence that both tVNS and iVNS activate the same afferent vagal projection sites (Butt et al., 2020). Both techniques modulate brain activity by activating both afferent and efferent vagus nerve fibres (Clancy et al., 2013; Colzato and Beste, 2020) and have shown to cause an increase in salivary alpha amylase concentrations (Warren et al., 2019).
However, mixed effects on the psychophysiological effects of vagus nerve responses have been reported. Whilst pupil size and P3 amplitude -an event-related potential elicited during decision making- are modulated by iVNS and in physiological VN responses (Burger et al., 2020), they are influenced by tVNS in some studies (Ventura-Bort et al., 2018; Sharon et al., 2021), but not in others (Warren et al., 2019). These observations suggest that although there is potential for tVNS to mimic iVNS, it is possible that the tVNS effect may be lower given the lack of direct stimulation of the vagus nerve, which is deep-seated in the neck within the carotid sheath.
Vagus Nerve Stimulation: Anti-Inflammatory and Systemic Effects
Microglia and astrocytes contribute to normal brain function. Microglia have a high expression of α2 and β1 adrenoreceptors, and NE promotes BDNF production in these cells. This signalling has been shown to be essential in learning-related synapse formation in mice (Parkhurst et al., 2013).
LC varicosities are highly associated with perivascular astrocyte end feet, exposing astrocytes to NE through volume transmission. Astrocytes support metabolic function of neurons and uptake of glutamate, which are enhanced by the activation of α1, α2 and β1 adrenergic receptors (O’Donnell et al., 2012). In the dentate gyrus of the hippocampus in mice, glycogen phosphorylase activation is enhanced by NE, supporting excitatory neurotransmission by making glucose more available to neurons (Harley, 2007).
Neuroinflammation is a pathological feature of many neurodegenerative diseases, including AD (Perry et al., 2007; Heneka et al., 2015). Microglia are involved in neuroinflammation, with microglial activation occurring due to insults such as bacterial infection or circulating cytokines inducing a pro-inflammatory phenotype. The resultant cycle of cytokine release and activation of additional microglia leads to chronic neuroinflammation, increasing the risk of neurodegeneration.
NE acting on microglia causes a suppression of proinflammatory cytokine signalling including IL-1, IL-6, TNF-α and inflammatory nitric oxide, through suppression of gene transcription (Mori et al., 2002), NE also upregulates gene transcription of anti-inflammatory molecules such as HSP-70 and MCP-1 in astrocytes and microglia (Heneka et al., 2010; Chalermpalanupap et al., 2013). The loss of LC neurons and the consequent reduction of NE anti-inflammatory signalling on neuroglia may thus be a likely contributor to the inflammation observed in brains with advanced Alzheimer’s disease [reviewed in (Arranz and de Strooper, 2019)].
Research also indicates an anti-inflammatory role for vagus nerve efferent signalling effects in the periphery, through acetylcholine release acting on tissue macrophages. This reduces cytokine synthesis and release similar to the effects on microglia. However, in the cholinergic anti-inflammatory pathway there is spleen involvement (Tracey, 2002), and further research will be required to establish whether the spleen is involved in the development of AD through Aβ accumulation (Yu et al., 2022) and whether VNS could improve the physiological capacity of the spleen to clear circulating Aβ. A reduction in cytokines including IL-6 and TNFα as a result of VNS has been measured in small-scale studies with patients with rheumatoid arthritis (Koopman et al., 2016), Crohn’s disease (Sinniger et al., 2020) and irritable bowel syndrome (Breit et al., 2018; Johnson and Wilson, 2018).
The peripheral effects of VNS are also highlighted by a study showing an interaction between the central sympathetic system and the parasympathetic VN to control arthritic joint inflammation (Bassi et al., 2017). iVNS in rats modulated arthritic joint inflammation through an afferent pathway mediated by LC activity. Afferent vagal stimulation activated two sympatho-excitatory brain areas, the paraventricular hypothalamic nucleus and the LC, the latter being essential for vagal control of arthritic joint inflammation.
The authors showed that the LC could provide peripheral neuromodulation and reduced arthritic joint inflammation by increasing NE levels in the synovial fluid, leading to a reduction synovial inflammatory cytokines concomitant with a reduction of leukocytes in the synovial microcirculation. A reduction in peripheral inflammation may have an overall positive effect on the progression of AD (Perry et al., 2007).
Furthermore, it has been recently reported that in freely moving rats 2 h of iVNS -either a rapid stimulation cycle (7s on/18s off) or a standard stimulation cycle (30 s on/300 s off)- caused a significant reduction of body temperature (3°C and 1°C, respectively). This effect was sustained in animals treated with the NE neurotoxin DSP-4; thus, although the LC does not seem to mediate this effect, VNS could interact with other neurotransmitter systems, including cholinergic, GABAergic and serotonergic, and indirectly activate the hypothalamus which potentially could mediate the body cooling (Larsen et al., 2017). As these results show, it will be essential to consider the systemic impact on VNS to address their positive or negative contribution to memory modulation, AD pathology and any secondary effects.
Neurons, Memory and Plasticity
Norepinephrine (NE) signals through G-protein coupled adrenergic receptors and its downstream effects can modulate the function of neuronal populations via effects on glia described above, or directly by synaptic mechanisms or changes in neuronal excitability. Neuronal effects of NE are highly varied between brain regions and adrenoreceptor subtype. For example, NE actions on α2-adrenoreceptors can increase network activity in the prefrontal cortex, but reduce excitatory transmission in neocortical and hippocampal pyramidal neurons, by limiting neurotransmitter release (O’Donnell et al., 2012).
Neuronal plasticity is a correlate of learning and memory. A widely researched mechanism of plasticity in hippocampal and cortical synapses involves the enhancement of synaptic efficacy through insertion of postsynaptic glutamate receptors of the AMPA subtype. Late-phase LTP in CA3-CA1 hippocampal synapses is a longer lasting potentiation dependent on protein synthesis. NE activates PKA which in turn phosphorylates AMPA receptors leading to their insertion in the plasma membrane (Hu et al., 2007).
In the amygdala, LC-derived NE is hypothesised to consolidate emotionally stressful experiences by inducing late phase LTP (Hassert et al., 2004; Zuo et al., 2007). There is evidence that VNS can promote plasticity between the ventromedial prefrontal cortex and the basolateral amygdala, reflected by extinction of a conditioned fear response (Peña et al., 2014; Alvarez-Dieppa et al., 2016).
Interestingly, selective optogenetic activation of LC-TH+ (dopamine releasing) neurons in mice enhanced synaptic function in the hippocampus and caused over 24 h persistence of an “everyday” type previously encoded memory, suggesting that LC stimulation can act as neuromodulator to promote the consolidation of hippocampal dependent memory. Thus, VNS may also allow native neuromodulation of memory pathways via dopaminergic signalling (Takeuchi et al., 2016).
The direct effects of NE acting on neurons are complex but appear to balance neuronal excitation and inhibition alongside neuroglial regulation [reviewed in (O’Donnell et al., 2012)]. Whether increased NE signalling induces potentiation or synaptic depression may depend on environmental factors, NE receptor subtype and intracellular signalling cascades specific to regions of the brain. Together, these effects modulate neuroplasticity in a region-specific manner tuned to autonomic regulation.
reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098960/
Original Research: Closed access.
“Vagus nerve stimulation drives selective circuit modulation through cholinergic reinforcement” by Cristin Welle et al. Neuron