CBF oscillations induced by trigeminal nerve stimulation protect the pericontusional penumbra in traumatic brain injury complicated by hemorrhagic shock

Traumatic peri-contusional penumbra represents crucial targets for therapeutic interventions after traumatic brain injury (TBI). Current resuscitative approaches may not adequately alleviate impaired cerebral microcirculation and, hence, compromise oxygen delivery to peri-contusional areas. Low-frequency oscillations in cerebral blood flow (CBF) may improve cerebral oxygenation in the setting of oxygen deprivation. However, no method has been reported to induce controllable oscillations in CBF and it hasn’t been applied as a therapeutic strategy. Electrical stimulation of the trigeminal nerve (TNS) plays a pivotal role in modulating cerebrovascular tone and cerebral perfusion. We hypothesized that TNS can modulate CBF at the targeted frequency band via the trigemino-cerebrovascular network, and TNS-induced CBF oscillations would improve cerebral oxygenation in peri-contusional areas. In a rat model of TBI complicated by hemorrhagic shock, TNS-induced CBF oscillations conferred significant preservation of peri-contusional tissues leading to reduced lesion volume, attenuated hypoxic injury and neuroinflammation, increased eNOS expression, improved neurological recovery and better 10-day survival rate, despite not significantly increasing CBF as compared with those in immediate and delayed resuscitation animals. Our findings indicate that low-frequency CBF oscillations enhance cerebral oxygenation in peri-contusional areas, and play a more significant protective role than improvements in non-oscillatory cerebral perfusion or volume expansion alone.

Neuroimaging and neurotherapeutics for Attention Deficit Hyperactivity Disorder (ADHD)

This paper reviews the functional magnetic resonance imaging (fMRI) literature of Attention Deficit Hyperactivity Disorder (ADHD) of the past three decades and the modern neurotherapies that have used these biomarkers as targets for treatment. Meta-analyses of task-based fMRI studies have shown functional abnormalities in different domain-dependent frontal, striatal, parietal, and cerebellar regions in ADHD. Resting state fMRI studies confirm abnormalities in different fronto-striato-parietal cognitive control, dorsal and ventral attention networks. The frontal parts of these networks have been targeted by neurotherapeutics. Only three small-numbered studies so far have applied functional near infrared spectroscopy (NIRS) and fMRI-Neurofeedback to ADHD. Studies have mostly shown feasibility and some promising effects on clinical, cognitive or imaging measures which invite further testing in larger samples. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) or inferior frontal cortex (IFC) has not shown promising effects so far on improving cognition or symptoms. Eighteen studies tested the effects of single or multi-session transcranial direct current stimulation (tDCS) of mostly left DLPFC on mostly cognitive functions with fewer studies targeting right DLPFC or IFC. Our meta-analysis of tDCS studies shows relatively small effects of improvement of cognitive function while insufficient studies have tested clinical efficacy. A proof of concept study of trigeminal nerve stimulation (TNS) showed promising medium size effects for improving clinical symptoms but requires replication in larger samples. In conclusion, neurotherapies are attractive due to minimal side effects and potential longer-term effects on brain plasticity which drugs cannot offer; however, they are still in their infancy. They require systematic testing of optimal protocols in large samples, including optimal site of stimulation/neurofeedback, optimal frequency of treatment sessions, or optimal stimulation amplitude. Importantly, they will need to show potential for individualised treatment by providing understanding of treatment response prediction.

Neurotherapeutics for Attention Deficit/Hyperactivity Disorder (ADHD): A Review

This review focuses on the evidence for neurotherapeutics for attention deficit/hyperactivity disorder (ADHD). EEG-neurofeedback has been tested for about 45 years, with the latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly the dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has been shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.

Trigeminal nerve stimulation: a recently approved treatment approach in attention deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) with its high prevalence is a growing area of concern and research, whereas exact underlying pathophysiology remains unknown. Behavioral therapy and multiple medications include methylphenidate, atomoxetine, and amphetamines while trigeminal nerve stimulator (TNS) is the first medical device in ADHD with FDA approval. The aim of this article is to evaluate the latest studies in this field.

Neurotherapeutics for Attention Deficit Hyperactivity Disorder (ADHD): a Review

This review focuses on the evidence for neurotherapeutics for Attention Deficit Hyperactivity Disorder (ADHD). EEG-Neurofeedback has been tested for about 45 years with latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.

Non-Invasive Rhythmic Musical-Electric Trigeminal Nerve Stimulation Improves Consciousness in Patients with Disorders of Consciousness

Disorders of consciousness (DOC) are often accompanied by aberrant oscillatory neural activity in the thalamus and cerebral cortex. Patient-friendly non-invasive treatments targeting this functional anomaly are still missing. We propose and validate a novel approach that aims to restore DOC patients’ thalamocortical oscillations by combining rhythmic trigeminal-nerve stimulation (TNS) with comodulated musical stimulation. In a cluster-randomized, placebo-controlled, double-blinded, pretest-posttest clinical study, we show that application of this multisensory approach for 40 min on five consecutive days reliably leads to long-lasting improvements in DOC patients’ consciousness (assessed with Coma Recovery Scale-Revised) and oscillatory brain activity at the musical-electric TNS frequency (assessed with electroencephalography and a novel rhythmic auditory-speech paradigm). We found diagnostic improvement in 47% of patients in minimally conscious state and a positive relationship between patients’ behavioral and neural improvements. Based on this evidence we argue that non-invasive musical-electric TNS may serve as an effective patient-friendly DOC treatment and suggest frequency-specific oscillatory neural enhancement as its mode of action.

CBF Oscillations Induced by Trigeminal Nerve Stimulation Protect the Pericontusional Penumbra in Traumatic Brain Injury Complicated By Hemorrhagic Shock

Traumatic peri-contusional penumbra represents crucial targets for therapeutic interventions after traumatic brain injury (TBI). Current resuscitative approaches may not adequately alleviate impaired cerebral microcirculation and, hence, compromise oxygen delivery to peri-contusional areas. Low-frequency oscillations in cerebral blood flow (CBF) may improve cerebral oxygenation in the setting of oxygen deprivation. However, no method has been reported to induce controllable oscillations in CBF and it hasn’t been applied as a therapeutic strategy. Electrical stimulation of the trigeminal nerve (TNS) plays a pivotal role in modulating cerebrovascular tone and cerebral perfusion. We hypothesized that TNS can modulate CBF at the targeted frequency band via the trigemino-cerebrovascular network, and TNS-induced CBF oscillations would improve cerebral oxygenation in peri-contusional areas. In a rat model of TBI complicated by hemorrhagic shock, TNS-induced CBF oscillations conferred significant preservation of peri-contusional tissues leading to reduced lesion volume, attenuated hypoxic injury and neuroinflammation, increased eNOS expression, improved neurological recovery and better 10-day survival rate, despite not significantly increasing CBF as compared with those in immediate and delayed resuscitation animals. Our findings indicate that low-frequency CBF oscillations enhance cerebral oxygenation in peri-contusional areas, and play a more significant protective role than improvements in non-oscillatory cerebral perfusion or volume expansion alone.

Value of Intraoperative Monitoring of the Trigeminal Nerve in Detection of a Superiorly Displaced Facial Nerve During Surgery for Large Vestibular Schwannomas

ObjectiveTo investigate the role of trigeminal and facial nerve monitoring in the early identification of a superiorly displaced facial nerve.Patients and MethodsThis prospective study included 24 patients operated for removal of large vestibular schwannomas (VS). Electromyographic (EMG) events recorded after mapping the superior surface of the tumor were evaluated by analyzing the latencies of the responses from the masseter and facial nerve innervated muscles.ResultsThe latency of the recorded compound muscle action potential (CMAP) from the masseter muscle was 3.6 ±0.5 msec, and of the simultaneously recorded volume conducted responses from the frontalis, o.oculi, nasalis, o.oris and mentalis muscles were 4.6 ±0.9, 4.1 ±0.7, 3.9 ±0.4, 4.3 ±0.8 and 4.5 ±0.6 msec respectively after trigeminal nerve stimulation in 24 (100%) patients. In 6 (25%) patients, the mean latency of CMAP on the masseter was 3.6 ±0.5 msec, and the latencies of the CMAP from the frontalis, nasalis, o.oris and mentalis muscles were longer than those of the volume conduced responses (p=0.002; p=0.001; p< 0.001; and p=0.015 respectively) indicating stimulation of both nerves (trigemino-facial EMG response). All patients with this response were later confirmed anatomically to have an AS displaced facial nerve. ConclusionUnderstanding the trigemino-facial EMG response is of value in identifying an AS displaced facial nerve; in preventing electrophysiological confusion between the trigeminal and the facial nerves; and in detecting the presence of volume conducted contributions in the measured facial nerve CMAP at the end of surgery.