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Initial studies suggested that the fluctuations in the quantity, variety, and composition of the gut microbiota can significantly affect disease processes. This change in the gut microbiota causing negative health benefits was coined dysbiosis. Initial research focused on gastrointestinal illnesses. However, the gut microbiome was found to affect more than just gastrointestinal diseases. Numerous studies have proven that the gut microbiome can influence neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.

Background Transcranial focused ultrasound (tFUS) is a noninvasive brain stimulation method that may modulate deep brain structures. This study investigates whether sonication of the right anterior thalamus would modulate thermal pain thresholds in healthy individuals. Methods We enrolled 19 healthy individuals in this three-visit, double-blind, sham-controlled, crossover trial. Participants first underwent a structural MRI scan used solely for tFUS targeting. They then attended two identical experimental tFUS visits (counterbalanced by condition) at least one week apart. Within the MRI scanner, participants received two, 10-min sessions of either active or sham tFUS spread 10 min apart targeting the right anterior thalamus [fundamental frequency: 650 kHz, Pulse repetition frequency: 10 Hz, Pulse Width: 5 ms, Duty Cycle: 5%, Sonication Duration: 30s, Inter-Sonication Interval: 30 s, Number of Sonications: 10, ISPTA.0 995 mW/cm2, ISPTA.3 719 mW/cm2, Peak rarefactional pressure 0.72 MPa]. The primary outcome measure was quantitative sensory thresholding (QST), measuring sensory, pain, and tolerance thresholds to a thermal stimulus applied to the left forearm before and after right anterior thalamic tFUS. Results The right anterior thalamus was accurately sonicated in 17 of the 19 subjects. Thermal pain sensitivity was significantly attenuated after active tFUS. The pre-post x active-sham interaction was significant (F(1,245.95) = 4.03, p = .046). This interaction indicates that in the sham stimulation condition, thermal pain thresholds decreased 1.08 °C (SE = 0.28) pre-post session, but only decreased .51 °C (SE = 0.30) pre-post session in the active stimulation group. Conclusions Two 10-min sessions of anterior thalamic tFUS induces antinociceptive effects in healthy individuals. Future studies should optimize the parameter space, dose and duration of this effect which may lead to multi-session tFUS interventions for pain disorders.

Noninvasive low-intensity focused ultrasound pulsation (LIFUP) neuromodulation provides a unique approach to both investigating and treating the brain. This work describes a well-calibrated, simple-to-use ultrasound stimulation system for neuromodulation studies. It provides a single-element 650-kHz transducer design and a straightforward control mechanism, with extensive calibration and internal electronic monitoring to prevent unwanted over or under treatment. One goal of this approach is to relieve researchers of many of the details associated with developing their own exposure equipment. A unique transducer positioning system and distinctive MRI fiducial targets simplify alignment and targeting. The system design, control software, calibration, and alignment techniques are described in detail. Examples of transducer targeting and neurostimulation using the system are provided.

An ever-growing population experiences a wide range of psychopathologies, and there is now more than ever a need for clear differential diagnoses between disorders. Furthering this need is the fact that many psychological, psychiatric, and neurological disorders have overlapping features. Functional neuroimaging has been shown to differentiate not only between the function of different brain structures but also between the roles of these structures in functional networks. The aim of this article is to aid in the goal of parsing out disorders on the basis of specific symptom domains by utilizing the most recent literature on functional networks. Current literature on the role of brain networks in relation to different psychopathological symptom domains is examined and corresponding circuit-based therapies that have been or may be used to treat them are discussed. Research on depression, obsession and compulsions, addiction, anxiety, and psychosis is reviewed. An understanding of networks and their specific dysfunctions opens the possibility of a new form of psychopathological treatment.

This article summarizes the field of focused ultrasound for use in neuromodulation and discusses different ways of targeting, delivering, and validating focused ultrasound. A discussion is focused on parameter space and different ongoing theories of ultrasonic neuromodulation. Current and future applications of the technique are discussed.

Electroencephalography (EEG), easily deployed at the bedside, is an attractive modality for deriving quantitative biomarkers of prognosis and differential diagnosis in severe brain injury and disorders of consciousness (DOC). Prior work by Schiff has identified four dynamic regimes of progressive recovery of consciousness defined by the presence or absence of thalamically-driven EEG oscillations. These four predefined categories (ABCD model) relate, on a theoretical level, to thalamocortical integrity and, on an empirical level, to behavioral outcome in patients with cardiac arrest coma etiologies. However, whether this theory-based stratification of patients might be useful as a diagnostic biomarker in DOC and measurably linked to thalamocortical dysfunction remains unknown. In this work, we relate the reemergence of thalamically-driven EEG oscillations to behavioral recovery from traumatic brain injury (TBI) in a cohort of N = 38 acute patients with moderate-to-severe TBI and an average of 1 week of EEG recorded per patient. We analyzed an average of 3.4 hr of EEG per patient, sampled to coincide with 30-min periods of maximal behavioral arousal. Our work tests and supports the ABCD model, showing that it outperforms a data-driven clustering approach and may perform equally well compared to a more parsimonious categorization. Additionally, in a subset of patients (N = 11), we correlated EEG findings with functional magnetic resonance imaging (fMRI) connectivity between nodes in the mesocircuit-which has been theoretically implicated by Schiff in DOC-and report a trend-level relationship that warrants further investigation in larger studies.

BACKGROUND: This study sought to validate the clinical utility of multimodal magnetic resonance imaging (MRI) techniques in the assessment of neurodegenerative disorders. We intended to demonstrate that advanced neuroimaging techniques commonly used in research can effectively be employed in clinical practice to accurately differentiate heathy aging and dementia subtypes. METHODS: Twenty patients with dementia of the Alzheimer’s type (DAT) and 18 patients with Parkinson’s disease dementia (PDD) were identified using gold-standard techniques. Twenty-three healthy, age and sex matched control participants were also recruited. All participants underwent multimodal MRI including T1 structural, diffusion tensor imaging (DTI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). MRI modalities were evaluated by trained neuroimaging readers and were separately assessed using cross-validated, iterative discriminant function analyses with subsequent feature reduction techniques. In this way, each modality was evaluated for its ability to differentiate patients with dementia from healthy controls as well as to differentiate dementia subtypes. RESULTS: Following individual and group feature reduction, each of the multimodal MRI metrics except MRS successfully differentiated healthy aging from dementia and also demonstrated distinct dementia subtypes. Using the following ten metrics, excellent separation (95.5% accuracy, 92.3% sensitivity; 100.0% specificity) was achieved between healthy aging and neurodegenerative conditions: volume of the left frontal pole, left occipital pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, right planum temporale; perfusion of the left hippocampus and left occipital lobe; fractional anisotropy (FA) of the forceps major and bilateral anterior thalamic radiation. Using volume of the left frontal pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, perfusion of the left hippocampus and left occipital lobe; FA of the forceps major and bilateral anterior thalamic radiation, neurodegenerative subtypes were accurately differentiated as well (87.8% accuracy, 95.2% sensitivity; 85.0% specificity). CONCLUSIONS: Regional volumetrics, DTI metrics, and ASL successfully differentiated dementia patients from controls with sufficient sensitivity to differentiate dementia subtypes. Similarly, feature reduction results suggest that advanced analyses can meaningfully identify brain regions with the most positive predictive value and discriminant validity. Together, these advanced neuroimaging techniques can contribute significantly to diagnosis and treatment planning for individual patients.

The study investigated the effects of focused ultrasound on human brain tissue to assess intensities at which focused ultrasound might cause irreversible structural cell damage. FUS does not appear to cause significant heating or cavitation to brain tissue when Ispta remains below 25 W/cm2. However, as the tissue was fixed immediately post-sonication, there was not sufficient time for apoptosis to develop, leaving open the possibility that a lower intensity over a longer period of time may cause stress and damage to the cell, leading to its eventual death. While additional studies should continue to further ensure the safety of this novel and important technology, this furthers the notion that, at the current FDA-approved levels, and potentially beyond, tFUS is likely a safe clinical technology.

In unconscious and non-communicative patients assessing the minimal behavioral change that patients themselves perceive as beneficial is not possible. In order to overcome this issue, we propose a novel combinatorial approach, leveraging international diagnostic guidelines, to create a probability-based minimal clinically significant change index for the most commonly used scale in patients with a disorders of consciousness.

Anxiety Disorders are prevalent and often chronic, recurrent conditions that reduce quality of life. The first-line treatments, such as serotonin reuptake inhibitors and cognitive behavioral therapy, leave a significant proportion of patients symptomatic. As psychiatry moves toward targeted circuit-based treatments, there is a need for a theory that unites the phenomenology of anxiety with its underlying neural circuits. The Alarm, Belief, Coping (ABC) theory of anxiety describes how the neural circuits associated with anxiety interact with each other and domains of the anxiety symptoms, both temporally and spatially. The latest advancements in neuroimaging techniques offer the ability to assess these circuits in vivo. Using Neurosynth, a large open-access meta-analytic imaging database, the association between terms related to specific neural circuits was explored within the ABC theory framework. Alarm-related terms were associated with the amygdala, anterior cingulum, insula, and bed nucleus of stria terminalis. Belief-related terms were associated with medial prefrontal cortex, precuneus, bilateral temporal poles, and hippocampus. Coping-related terms were associated with the ventrolateral and dorsolateral prefrontal cortices, basal ganglia, and anterior cingulate. Neural connections underlying the functional neuroanatomy of the ABC model were observed. Additionally, there was considerable interaction and overlap between circuits associated with the symptom domains. Further neuroimaging research is needed to explore the dynamic interaction between the functional domains of the ABC theory. This will pave the way for probing the neuroanatomical underpinnings of anxiety disorders and provide an evidence-based foundation for the development of targeted treatments, such as neuromodulation.

Objective Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing. Methods Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others. Results With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS. Significance This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

Deep brain nuclei are integral components of large-scale circuits mediating important cognitive and sensorimotor functions. However, because they fall outside the domain of conventional non-invasive neuromodulatory techniques, their study has been primarily based on neuropsychological models, limiting the ability to fully characterize their role and to develop interventions in cases where they are damaged. To address this gap, we used the emerging technology of non-invasive low-intensity focused ultrasound (LIFU) to directly modulate left lateralized basal ganglia structures in healthy volunteers. During sonication, we observed local and distal decreases in blood oxygenation level dependent (BOLD) signal in the targeted left globus pallidus (GP) and in large-scale cortical networks. We also observed a generalized decrease in relative perfusion throughout the cerebrum following sonication. These results show, for the first time using functional MRI data, the ability to modulate deep-brain nuclei using LIFU while measuring its local and global consequences, opening the door for future applications of subcortical LIFU.

ObjectiveLow-Intensity Focused Ultrasound Pulsations (LIFUP) is a promising new potential neuromodulation tool. However, the safety of LIFUP neuromodulation has not yet been adequately assessed. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of LIFUP neuromodulation. Because the brain tissue in these patients will be removed, histological changes in tissue after LIFUP can be examined. Evidence of effective neuromodulation was assessed using functional MRI and EEG, while further potential safety concerns were assessed using neuropsychological testing.MethodsEEG, functional MRI, and neuropsychology were assessed in six patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, LIFUP was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. EEG was recorded using the Electrical Geodesics EGI 256 channel system. Histological changes were assessed using hematoxylin and eosin staining, among others.ResultsLIFUP was not able to modulate the BOLD signal on fMRI in a reliable and consistent manner. The EEG data that was available did not demonstrate a change in activity after LIFUP in all but one subject. Likewise, the neuropsychology testing did not show any statistically significant changes in any test, except for a slight decrease in performance on the one test after LIFUP. Lastly, the histology did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive.SignificanceThe safety in the histology was the primary endpoint, and as such, longer exposure at the highest intensity levels will be administered moving forward.Key PointsLIFUP is a novel brain stimulation technique with not yet fully established safety guidelines.LIFUP was administered to patients electing to undergo resective brain surgery.LIFUP does not appear to cause damage to tissue.Longer exposure times are needed to further show safety at these intensity levels.

Introduction: In multiple animal models of ischemic stroke, cerebellar fastigial nucleus stimulation (FNS) via implanted electrode has been shown to exert strong neuroprotective and collateral enhancement effects. Translational studies of FNS have been precluded due to the invasive nature of direct electrical stimulation. Recently, low-intensity focused ultrasound pulsation (LIFUP) has been used to stimulate deep hemispheric targets. Identifying achievable anatomic trajectories for LIFUP delivery is required for human trials. Method: Sagittal brain MRI T1 from 10 patients were analyzed. Potential pathways from the suboccipital (SO) region (transducer placement site) to the roof of the 4 th ventricle (location of FN) were traced, evaluating paths both via the thinnest portion of the occipital bone (OB) and via the transforaminal window (TFW). Interindividual variations in trajectory distances (cm), thickness of the OB through which the beam passes (cm), and the projected neck flexion degree from neutral position required to achieve a TFW path were measured. Results: An achievable anatomic pathway for stimulation of the FN via LIFUP was identified in 100% of patients (Fig 1). In standard MR positioning, 90% had an available path through thin portions of the OB and 10% had a projected path through TFW. The mean distance from the skin at the SO region to the roof of 4 th ventricle/FN was 7.2 cm (± 0.64cm). The mean OB thickness traversed by the beam was 0.3cm (±0.1). The projected required neck flexion to enable a TFW in all subjects was mean 9.3° (±5°). Conclusions: The distance for the LIFUP beam to travel from skin surface to FN via a suboccipital approach is well within the LIFUP penetration depth and all individuals had an accessible trajectory via the TFW through attainable degrees of head flexion, affording minimal ultrasonic energy dispersion and maximal focality. Ultrasound stimulation of fastigial nucleus is a feasible treatment strategy in human acute ischemic stroke.

A 29-year-old woman presented with head and neck dystonia, as well as functional seizures. The patient was an active military service member with a history of combat-related trauma. Resting blood oxygen level dependent (BOLD) functional MRI (fMRI) scans of the brain demonstrated an increased anterior cingulate component of the salience network and hyper-connectivity between the insula and cingulate. Following neurological and psychiatric evaluation, she was diagnosed with dissociative post-traumatic stress disorder, partially presenting as a functional movement disorder. Inhibitory repetitive transcranial magnetic stimulation (rTMS) was prescribed with the anterior cingulate as the primary target, and supplementary motor and premotor cortices as secondary targets. The treatment was intended to suppress tremors both directly and indirectly. Thirty-six sessions later, her symptoms were in remission, and she returned to active duty. This case demonstrates the potential efficacy of fMRI-guided rTMS in the treatment of dissociative PTSD.