The most common GI disorder, impacting approximately 7-21% of the (484) population, is IBS [88]. Core pathophysiological mechanisms of IBS include visceral hypersensitivity (or modified pain perception) (485), weakened brain-gut communication, changes in microbiota composition and gastrointestinal motility (486) [88]. Visceral hypersensitivity is considered the primary culprit(487) behind abdominal pain or discomfort, believed to arise (488) from heightened intestinal permeability and activation of gut mucosal immunity (489).
Serotonin (5-hydroxytryptamine; 5-HT) acts as a prevalent transmitter in the gastrointestinal (491) system, predominantly produced by enteroendocrine (EC) cells residing in the gut epithelium, accounting for 90%-95% of the total 5-HT (492) reservoir within the human organism. The synthesis of 5-HT is regulated by tryptophan hydroxylase (TPH) (493) [89]. Moreover, the gut microbiota significantly influences 5-HT synthesis and release by modulating (494) EC cells In a rat model of post-infectious irritable bowel syndrome (IBS), quercetin demonstrates (495) the capability to reduce the density of EC cells and downregulate TPH expression. Consequently, quercetin administration leads to a decrease in 5-HT levels (496) and a mitigation of visceral pain sensations experienced by IBS-afflicted rodents (497) [90].
bilateral symba conchas or undergoing sham electrical stimulation (via the elbow) (501). The application of taVNS resulted in an escalation in the weekly count of complete spontaneous bowel movements, alleviation of abdominal (502) discomfort, and enhancement in both overall IBS symptoms and quality of life. Furthermore, an improvement in (503) the perception of rectal stimuli and the relaxation of the internal anal sphincter triggered by rectal distention was noted (504).
A method involving stimulation of the auricular vagal nerve (aVNS), using consistent parameters, was (509) discovered to accelerate the movement of the lower part of the colon, which lacks direct innervation by the vagus nerve (510). This effect was accompanied by a simultaneous rise in the activity of neurons in the nucleus tractus solitarius (NTS) (511) in a mouse model experiencing constipation induced by opioids. These observations suggest that aVNS could impact the motility and sensation of the colorectum (512) through both the vago-vagal and vago-sacral routes (513).
Conditions such as Crohn's Disease (CD), Ulcerative Colitis (UC), and Microscopic Colitis (MC) fall under the umbrella term of inflammatory bowel disorder (529).
Vagal nerve stimulation possesses the capability to diminish inflammation within the intestinal tract through various mechanisms (536). Firstly, it initiates signals via afferent neurons, prompting the brain to engage efferent pathways (537), potentially involving sympathetic responses from the central nervous system. Secondly, it directly activates efferent pathways (538) of the vagus nerve. Thirdly, it triggers the release of neurotransmitters from the peripheral terminals (539) of vagal afferents. Support for the influence of vagal efferents on enteric
neurons stems from observations indicating that (540) intestinal inflammation instigates a circuitry mediated by the vagus nerve, resulting in the activation of motor neurons (541) associated with the inflamed region of the gut (542).
Gastroesophageal Reflux Disease (GERD) stands as a persistent state wherein the regurgitation (549) of stomach substances into the esophagus generates discomfort or obstructions. It is categorized (550) into three forms: non-erosive reflux disorder (NERD), erosive esophagitis, and Barrett's esophagus (551). Principal GERD pathophysiological mechanisms consist of (a) compromised esophageal evacuation (552) owing to debilitated esophageal motility (e.g., feeble esophageal peristalsis); (b) malfunction of the anti-reflux (553) barricade at the esophagogastric junction (EGJ) caused by hypotonic lower (554) esophageal sphincter (LES), transient LES relaxations (tLESRs), and/or discordance (555) between LES and the crural diaphragm (e.g., the existence of hiatal hernia); and c) downstream (556) gastric aspects: postponed gastric emptying and gastric acid recess (557).
The pressure recorded via esophageal manometry, pertaining to the lower esophageal sphincter (LES) (574), encompasses the collective force exerted by both the LES and the crural diaphragm. It is speculated that certain stimulations (575) may elevate the crural diaphragm pressure, yet empirical evidence supporting this hypothesis is lacking (576). In a preliminary open-label investigation, transcutaneous abdominal electrical stimulation demonstrated a (577) noteworthy reduction exceeding 50% in acid exposure duration and DeMeester score among (578) GERD patients who exhibited resistance to conventional proton pump inhibitor therapy (579) [110].
Aligned with the concept of modified cortical evolution in ASD, parts of the frontal (612) and prefrontal cortex linked to linguistic expression and interpersonal abilities undergo a surge (613) in synaptic formation and adaptability during the initial three years of life, which is typically when signs of autism (614) associated with these functions emerge [122].
Repetitive transcranial magnetic stimulation (rTMS) involves the application of sequences of multiple TMS (617) pulses across a specific cerebral area, with pulse frequencies spanning from 0.5 to 20 Hz [124]. When administered at lower frequencies (618) , rTMS induces sustained inhibition of cortical excitability within the designated cortical area (619).
The employment of transcranial direct current stimulation (tDCS) has the potential to enhance or diminish (632) cortical excitability and/or specific brain oscillations. Additionally, tDCS can influence gamma activity (633). Transcranial random noise stimulation (tRNS) employs a weak-level, stochastic biphasic electrical flow (634) applied at the scalp within a frequency range of 0.1 to 640 Hz [130] (635) . While both tDCS and tRNS effectively alter cortical excitability and plasticity mechanisms (636), only transcranial alternating current stimulation (tACS) has been directly associated with regulating oscillatory dynamics (637) at specific frequencies, exhibiting
its impact on gamma activity in both animal and human studies (638). tACS utilizes sinusoidal or biphasic currents set at predetermined frequencies to interact with (639) the brain's inherent oscillatory patterns, synchronizing neuronal firing to the applied electric field and inducing significant neuromodulatory effects [131] (640-642). These enhancements induced by gamma tACS (643) demonstrate a strong correlation with changes in blood oxygenation level-dependent (BOLD) activity within the (644) stimulated primary motor cortex (M1) region [132]. Moreover, higher-order cognitive functions have been targeted using (645) gamma-entrainment approaches with tACS. Hoy et al. identified a discernible (646) enhancement in working memory performance following gamma-tACS application [133]. Given the overall diminished (647) gamma activity observed in autism spectrum disorder (ASD), the application of gamma-tACS to these regions (648) may offer the potential to synchronize and partially restore typical gamma activity in individuals with ASD (649-650).
Parkinson's condition manifests as a persistent, advancing ailment marked by the decline (652) of numerous dopaminergic neurons within the basal ganglia network. The absence of dopamine (653) exacerbates observable motor indications like sluggish movement, shaking, rigidity, (654) instability in posture, and walking difficulties [134]. Studies both epidemiological and clinical in (655) nature have recently hinted at the emergence of what's termed as "mild cognitive impairment" (MCI) as a multifaceted feature seen in the initial phases of Parkinson's disease (656-657) [135].
In reference to DBS within the subthalamic nucleus for Parkinson's ailment (667), an escalated firing pace is discerned within the globus pallidus (668), notwithstanding the inhibition of stimulating STN neurons directing to the globus pallidus [138]. Moreover, (669) globus pallidus neurons showcase spike behavior that synchronizes with the stimulus pulses. DBS (670)is theorized to divide dendritic and somatic function from axonal output function (671), dampening the former while driving the latter at or near the stimulation frequency [139] (672).
Shirota and colleagues delved into the effectiveness and impact of varying stimulation frequencies of rTMS on the (674) SMA in individuals with PD. Findings indicated a reduction (enhancement) of 6.84 units in the Unified Parkinson's Disease Rating Scale (675) (UPDRS) part III scores among participants in the 1 Hz cohort during the final assessment (676) (12 weeks post-intervention) [140]. Despite the lack of definitive understanding regarding the molecular mechanisms driving these alterations (677), numerous hypotheses have been suggested (678).
Modifications in cortical excitability and neuroplasticity are significantly impacted by the availability of dopamine (688), with the utilization of dopaminergic treatment potentially altering the ensuing neurophysiological (689) and behavioral outcomes of stimulation (690) [143].
In terms of pathology, Alzheimer's Disease (AD) (695) is characterized by the existence of amyloid- (A) plaques outside cells and tau neurofibrillary tangles (NFT) inside neurons (696-697).
rTMS for the treatment of Alzheimer's disease (AD) demonstrated a significant enhancement in short-term cognitive (712) abilities among the participants. The effect size, measured by the standard mean difference (SMD) for both the Mini-Mental State Examination (713) (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (714), was calculated to be 0.42 (95% CI, 0.18 to 0.67, P = 0.0006) [151]. The mean change in MMSE scores pre and post-treatment was 1.08 (95% CI, 0.35 to 1.80) [152] (715). Notably, high-frequency TMS was identified as the most effective short-term intervention (716) for enhancing overall cognitive function when compared to various other electrical stimulation modalities (717). Moreover, statistically significant improvements in cognitive function were observed when stimulating multiple sites (718) (SMD = 0.47; 95% CI, 0.14 to 0.79; P = 0.005) compared to single-site stimulation (SMD = 0.24; 95% CI, -0.45 to 0.92; P = 0.50) (719). The cognitive scores tended to improve with longer-term treatment (720) (more than 10 sessions) and higher frequency (20 Hz versus 10 Hz or 1 Hz) (721) [151].
Transcranial direct current stimulation has additionally been employed (727)
Several studies on transcranial direct current stimulation (tDCS) have discovered that applying positive stimulation to the left dorsolateral prefrontal cortex (DLPFC) can notably diminish (729) depression ratings for a duration of approximately 30 days post-treatment [154]. Conversely, a meta-analysis (730) failed to detect any discernible impact on cognitive function unrelated to mood enhancement [155]. This suggests (731) that isolating a distinct cognitive effect of tDCS within the framework of a clinical study presents challenges due to overall cognitive (732) enhancements observed in patients throughout the trial. Enhancing the stimulation of DLPFC (733) with personalized approaches, alongside exploring further tDCS applications on various brain regions (734) associated with mood and emotion, like the parietal cortex [156], could potentially enhance the effectiveness of tDCS in treating depression (735-736).
Schizophrenia is often marked by shifts in cortical functional connections (738). Approximately 50% to 70% of individuals diagnosed with schizophrenia experience auditory verbal (739) hallucinations, which frequently show resistance to pharmaceutical treatments (740) [157].
Stimulating the anode (which excites) over the left DLPFC, combined with (748) cathodic (which inhibits) stimulation over the left temporal-parietal junction, displayed a notable decrease (749) in the frequency of auditory verbal hallucinations among individuals with schizophrenia (750) in a contemporary tDCS investigation [157].
Significantly, the reduction in auditory verbal hallucinations (751) endured for a period of three months subsequent to the conclusion of tDCS therapy (752).
enhancing its potential as a focal point for tDCS intervention. Anodal tDCS applied to the (754) left DLPFC demonstrated enhancement in probabilistic association acquisition among a subgroup of individuals diagnosed with schizophrenia (755) [162].
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