Current state of clinical ultrasound neuromodulation.

Unmatched by other non-invasive brain stimulation techniques, transcranial ultrasound (TUS) offers highly focal stimulation not only on the cortical surface but also in deep brain structures. These unique attributes are invaluable in both basic and clinical research and might open new avenues for treating neurological and psychiatric diseases. Here, we provide a concise overview of the expanding volume of clinical investigations in recent years and upcoming research initiatives concerning focused ultrasound neuromodulation. Currently, clinical TUS research addresses a variety of neuropsychiatric conditions, such as pain, dementia, movement disorders, psychiatric conditions, epilepsy, disorders of consciousness, and developmental disorders. As demonstrated in sham-controlled randomized studies, TUS neuromodulation improved cognitive functions and mood, and alleviated symptoms in schizophrenia and autism. Further, preliminary uncontrolled evidence suggests relieved anxiety, enhanced motor functions in movement disorders, reduced epileptic seizure frequency, improved responsiveness in patients with minimally conscious state, as well as pain reduction after neuromodulatory TUS. While constrained by the relatively modest number of investigations, primarily consisting of uncontrolled feasibility trials with small sample sizes, TUS holds encouraging prospects for treating neuropsychiatric disorders. Larger sham-controlled randomized trials, alongside further basic research into the mechanisms of action and optimal sonication parameters, are inevitably needed to unfold the full potential of TUS neuromodulation.

Novel ultrasound neuromodulation therapy with transcranial pulse stimulation (TPS) in Parkinson's disease: a first retrospective analysis.

BACKGROUND: Transcranial Pulse Stimulation (TPS) has been recently introduced as a novel ultrasound neuromodulation therapy with the potential to stimulate the human brain in a focal and targeted manner. Here, we present a first retrospective analysis of TPS as an add-on therapy for Parkinson's disease (PD), focusing on feasibility, safety, and clinical effects. We also discuss the placebo response in non-invasive brain stimulation studies as an important context. METHODS: This retrospective clinical data analysis included 20 PD patients who received ten sessions of TPS intervention focused on the individual motor network. Safety evaluations were conducted throughout the intervention period. We analyzed changes in motor symptoms before and after TPS treatment using Unified Parkinson's Disease Rating Scale part III (UPDRS-III). RESULTS: We found significant improvement in UPDRS-III scores after treatment compared to baseline (pre-TPS: 16.70 ± 8.85, post-TPS: 12.95 ± 8.55; p < 0.001; Cohen's d = 1.38). Adverse events monitoring revealed no major side effects. CONCLUSION: These preliminary findings suggest that TPS can further improve motor symptoms in PD patients already on optimized standard therapy. Findings have to be evaluated in context with the current literature on placebo effects.

Avoid or seek light - a randomized crossover fMRI study investigating opposing treatment strategies for photophobia in migraine.

BACKGROUND: Photophobia, the aberrantly increased sensitivity to light, is a common symptom in migraine patients and light discomfort is frequently found as a trigger for migraine attacks. In behavioral studies, planned exposure to light was found to reduce headache in migraine patients with photophobia, potentially by increasing habituation to this migraine trigger. Here, we aimed to elucidate neurophysiological mechanisms of light exposure versus light deprivation in migraine patients using functional magnetic resonance imaging (fMRI). METHODS: Ten migraine patients (9 female, age = 28.70 ± 8.18 years) and 11 healthy controls (9 female, age = 23.73 ± 2.24 years) spent one hour on 7 consecutive days exposed to flashing light (Flash) or darkness (Dark) using a crossover design with a wash-out period of 3 months. Study participants kept a diary including items on interictal and ictal photophobia, presence and severity of headache 7 days before, during and 7 days after the interventions. One week before and one day after both interventions, fMRI using flickering light in a block design was applied. Functional activation was analyzed at whole-brain level and habituation of the visual cortex (V1) was modeled with the initial amplitude estimate and the corrected habituation slope. RESULTS: Mean interictal photophobia decreased after both interventions, but differences relative to the baseline did not survive correction for multiple comparisons. At baseline, flickering light induced activation in V1 was higher in the patients compared to the controls, but activation normalized after the Flash and the Dark interventions. V1 habituation indices correlated with headache frequency, headache severity and ictal photophobia. In the Flash condition, the individual change of headache frequency relative to the baseline corresponded almost perfectly to the change of the habituation slope compared to the baseline. CONCLUSIONS: On average, light exposure did not lead to symptom relief, potentially due to the short duration of the intervention and the high variability of the patients' responses to the intervention. However, the strong relationship between visual cortex habituation and headache symptoms and its modulation by light exposure might shed light on the neurophysiological basis of exposure treatment effects. TRIAL REGISTRATION: NCT05369910 (05/06/2022, retrospectively registered).

Functional Specificity of TPS Brain Stimulation Effects in Patients with Alzheimer's Disease: A Follow-up fMRI Analysis.

INTRODUCTION: Transcranial pulse stimulation (TPS) has been recently introduced as a novel clinical brain stimulation technique based on highly focused ultrasound pressure pulses. In a first pilot study on clinical effects of navigated and focused ultrasound neuromodulation, a dichotomy of functional effects was found: patients with Alzheimer's disease improved cognition and language but deteriorated with visuo-constructive functions. METHODS: We analyzed changes in functional connectivity measured with functional magnetic resonance imaging (fMRI) using graph analysis of a visuo-constructive network in 18 patients with Alzheimer's disease. We calculated the network's global efficiency and tested for correlation with visuo-constructive test scores to explain this dichotomy. RESULTS: Important visuo-constructive network nodes were not stimulated in the pilot setting and correspondingly global efficiency of a visuo-constructive network was decreased after TPS therapy, compatible with a natural progress of the disease. A correlation between visuo-constructive scores and changes in global efficiency was found. CONCLUSION: Results argue for a high functional specificity of ultrasound-based neuromodulation with TPS.

Over the last decade, there has been growing interest in ultrasound-based non-invasive brain stimulation techniques in neuroscience and as a potential therapy for disorders of the brain. Transcranial pulse stimulation (TPS) has been introduced as an innovative neuromodulation technique, applying ultrashort pressure pulses through the skull into neural tissue with 3D navigation in real time. In the first clinical pilot study, patients suffering from Alzheimer's disease showed an increase in memory and language functions for up to 3 months after TPS therapy. However, visuo-constructive capacities (e.g., copying a geometrical figure) worsened. Notably, brain areas relevant for such processes had been left out during stimulation. This begged the question whether the brain areas that were targeted for brain stimulation as well as functional changes could explain this diverse response pattern. We therefore analyzed functional magnetic resonance data from patients. Specifically, we compared graph theoretical functional connectivity measures in a visuo-constructive network before and after TPS therapy. We found a decrease in connectivity in a central network node, which also correlated with visuo-constructive test scores. This deterioration is likely associated with normal disease progression. Together with the already reported improvement in global cognitive functions, these results argue for a functional specific effect of TPS.

Transcranial pulse stimulation (TPS) improves depression in AD patients on state-of-the-art treatment.

INTRODUCTION: Ultrasound-based brain stimulation is a novel, non-invasive therapeutic approach to precisely target regions of interest. Data from a first clinical trial of patients with Alzheimer's disease (AD) receiving 2-4 weeks transcranial pulse stimulation (TPS) have shown memory and cognitive improvements for up to 3 months, despite ongoing state-of-the-art treatment. Importantly, depressive symptoms also improved. METHODS: We analyzed changes in Beck Depression Inventory (BDI-II) and functional connectivity (FC) changes with functional magnetic resonance imaging in 18 AD patients. RESULTS: We found significant improvement in BDI-II after TPS therapy. FC analysis showed a normalization of the FC between the salience network (right anterior insula) and the ventromedial network (left frontal orbital cortex). DISCUSSION: Stimulation of areas related to depression (including extended dorsolateral prefrontal cortex) appears to alleviate depressive symptoms and induces FC changes in AD patients. TPS may be a novel add-on therapy for depression in AD and as a neuropsychiatric diagnosis.

First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain.

BACKGROUND: With the high spatial resolution and the potential to reach deep brain structures, ultrasound-based brain stimulation techniques offer new opportunities to non-invasively treat neurological and psychiatric disorders. However, little is known about long-term effects of ultrasound-based brain stimulation. Applying a longitudinal design, we comprehensively investigated neuromodulation induced by ultrasound brain stimulation to provide first sham-controlled evidence of long-term effects on the human brain and behavior. METHODS: Twelve healthy participants received three sham and three verum sessions with transcranial pulse stimulation (TPS) focused on the cortical somatosensory representation of the right hand. One week before and after the sham and verum TPS applications, comprehensive structural and functional resting state MRI investigations and behavioral tests targeting tactile spatial discrimination and sensorimotor dexterity were performed. RESULTS: Compared to sham, global efficiency significantly increased within the cortical sensorimotor network after verum TPS, indicating an upregulation of the stimulated functional brain network. Axial diffusivity in left sensorimotor areas decreased after verum TPS, demonstrating an improved axonal status in the stimulated area. CONCLUSIONS: TPS increased the functional and structural coupling within the stimulated left primary somatosensory cortex and adjacent sensorimotor areas up to one week after the last stimulation. These findings suggest that TPS induces neuroplastic changes that go beyond the spatial and temporal stimulation settings encouraging further clinical applications.

A New Rehabilitative Mechanism in Primary Motor Cortex After Peripheral Trauma.

Homuncular organization, i.e., the neuronal representation of the human body within the primary motor cortex, is one of the most fundamental principles of the human brain. Despite this, in rare peripheral nerve surgery patients, the transformation of a monofunctional (diaphragm activation) into a bifunctional motor area (diaphragm and arm activation is controlled by the same cortical area) has previously been demonstrated. The mechanisms behind this transformation are not fully known. To investigate this transformation of a monofunctional area we investigate functional connectivity changes in a unique and highly instructive pathophysiological patient model. These patients suffer from complete brachial plexus avulsion with arm paralysis and had been treated with reconnection of the end of the musculocutaneous nerve to the side of a fully functional phrenic nerve to regain function. Task-based functional connectivity between the arm representations and the diaphragm (phrenic nerve) representations were examined in six patients and 12 aged matched healthy controls at ultra-high field MRI while they either performed or tried isolated elbow flexion or conducted forced abdominal inspiration. Functional connectivity values are considerably increased between the diseased arm and the bilateral diaphragm areas while trying strong muscle tension in the diseased arm as compared to the healthy arm. This effect was not found as compared to the healthy arm in the patient group. This connectivity was stronger between ipsilateral than between corresponding contralateral brain regions. No corresponding differences were found in healthy subjects. Our data suggests that the increased functional connectivity between the deprived arm area and the diaphragm area drives biceps muscle function. From this findings we infer that this new rehabilitative mechanism in the primary motor cortex may establish new intrahemispheric connections within the brain and the motor cortex in particular to reroute the output of a completely denervated motor area. This study extend current knowledge about neuroplasticity within the motor cortex.

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy.

Ultrasound-based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham-controlled clinical studies.

Dopaminergic modulation of the praxis network in Parkinson's disease.

Apraxia is a deficit in central motor planning impairing praxis functions such as gesture production or tool use that affects a substantial number of patients with advanced Parkinson's disease. We investigated the functional connectivity of the praxis network in patients in early stages of Parkinson's disease having an increased risk for apraxia and evaluated the influence of dopaminergic therapy on praxis abilities and related networks. 13 patients with mild to moderate Parkinson's disease (ON and OFF dopaminergic therapy) and 13 healthy controls completed a praxis sensitive functional MRI task and apraxia assessments. Functional connectivity analyses included a graph theoretical approach analyzing the global efficiency within the praxis network followed by a seed-to-voxel functional connectivity analysis. Patients in the OFF but not in the ON state showed significantly lower praxis scores than controls. Patients in both states displayed higher global efficiency within the praxis network than controls revealing the bilateral supramarginal gyri as hubs. Seed-to-voxel functional connectivity analyses showed aberrations of right-hemispheric praxis areas in the OFF but not in the ON state. Patients in the ON state exhibited a significantly higher functional connectivity between the supramarginal gyrus and the primary motor cortex, basal ganglia, and frontal areas than in the OFF state. Dopaminergic therapy seems to normalize praxis abilities and related praxis networks in early stages of Parkinson's disease potentially by facilitating the propagation of long-term representations of object-related actions to motor execution areas.

Improving sensitivity, specificity, and reproducibility of individual brainstem activation.

Functional imaging of the brainstem may open new avenues for clinical diagnostics. However, for reliable assessments of brainstem activation, further efforts improving signal quality are needed. Six healthy subjects performed four repeated functional magnetic resonance imaging (fMRI) sessions on different days with jaw clenching as a motor task to elicit activation in the trigeminal motor nucleus. Functional images were acquired with a 7 T MR scanner using an optimized multiband EPI sequence. Activation measures in the trigeminal nucleus and a control region were assessed using different physiological noise correction methods (aCompCor and RETROICOR-based approaches with variable numbers of regressors) combined with cerebrospinal fluid or brainstem masking. Receiver-operating characteristic analyses accounting for sensitivity and specificity, activation overlap analyses to estimate the reproducibility between sessions, and intraclass correlation analyses (ICC) for testing reliability between subjects and sessions were used to systematically compare the physiological noise correction approaches. Masking the brainstem led to increased activation in the target ROI and resulted in higher values for the area under the curve (AUC) as a combined measure for sensitivity and specificity. With the highest values for AUC, activation overlap, and ICC, the most favorable physiological noise correction method was to control for the cerebrospinal fluid time series (aCompCor with one regressor). Brainstem motor nuclei activation can be reliably identified using high-field fMRI with optimized acquisition and processing strategies-even on single-subject level. Applying specific physiological noise correction methods improves reproducibility and reliability of brainstem activation encouraging future clinical applications.

The Impact of Echo Time Shifts and Temporal Signal Fluctuations on BOLD Sensitivity in Presurgical Planning at 7 T.

OBJECTIVES: Gradients in the static magnetic field caused by tissues with differing magnetic susceptibilities lead to regional variations in the effective echo time, which modifies both image signal and BOLD sensitivity. Local echo time changes are not considered in the most commonly used metric for BOLD sensitivity, temporal signal-to-noise ratio (tSNR), but may be significant, particularly at ultrahigh field close to air cavities (such as the sinuses and ear canals) and near gross brain pathologies and postoperative sites. MATERIALS AND METHODS: We have studied the effect of local variations in echo time and tSNR on BOLD sensitivity in 3 healthy volunteers and 11 patients with tumors, postoperative cavities, and venous malformations at 7 T. Temporal signal-to-noise ratio was estimated from a 5-minute run of resting state echo planar imaging with a nominal echo time of 22 milliseconds. Maps of local echo time were derived from the phase of a multiecho GE scan. One healthy volunteer performed 10 runs of a breath-hold task. The t-map from this experiment served as a criterion standard BOLD sensitivity measure. Two runs of a less demanding breath-hold paradigm were used for patients. RESULTS: In all subjects, a strong reduction in the echo time (from 22 milliseconds to around 11 milliseconds) was found close to the ear canals and sinuses. These regions were characterized by high tSNR but low t-values in breath-hold t-maps. In some patients, regions of particular interest in presurgical planning were affected by reductions in the echo time to approximately 13-15 milliseconds. These included the primary motor cortex, Broca's area, and auditory cortex. These regions were characterized by high tSNR values (70 and above). Breath-hold results were corrupted by strong motion artifacts in all patients. CONCLUSIONS: Criterion standard BOLD sensitivity estimation using hypercapnic experiments is challenging, especially in patient populations. Taking into consideration the tSNR, commonly used for BOLD sensitivity estimation, but ignoring local reductions in the echo time (eg, from 22 to 11 milliseconds), would erroneously suggest functional sensitivity sufficient to map BOLD signal changes. It is therefore important to consider both local variations in the echo time and temporal variations in signal, using the product metric of these two indices for instance. This should ensure a reliable estimation of BOLD sensitivity and to facilitate the identification of potential false-negative results. This is particularly true at high fields, such as 7 T and in patients with large pathologies and postoperative cavities.

The clinical relevance of distortion correction in presurgical fMRI at 7T.

Presurgical planning with fMRI benefits from increased reliability and the possibility to reduce measurement time introduced by using ultra-high field. Echo-planar imaging suffers, however, from geometric distortions which scale with field strength and potentially give rise to clinically significant displacement of functional activation. We evaluate the effectiveness of a dynamic distortion correction (DDC) method based on unmodified single-echo EPI in the context of simulated presurgical planning fMRI at 7T and compare it with static distortion correction (SDC). The extent of distortion in EPI and activation shifts are investigated in a group of eleven patients with a range of neuropathologies who performed a motor task. The consequences of neglecting to correct images for susceptibility-induced distortions are assessed in a clinical context. It was possible to generate time series of EPI-based field maps which were free of artifacts in the eloquent brain areas relevant to presurgical fMRI, despite the presence of signal dropouts caused by pathologies and post-operative sites. Distortions of up to 5.1mm were observed in the primary motor cortex in raw EPI. These were accurately corrected with DDC and slightly less accurately with SDC. The dynamic nature of distortions in UHF clinical fMRI was demonstrated via investigation of temporal variation in voxel shift maps, confirming the potential inadequacy of SDC based on a single reference field map, particularly in the vicinity of pathologies or in the presence of motion. In two patients, the distortion correction was potentially clinically significant in that it might have affected the localization or interpretation of activation and could thereby have influenced the treatment plan. Distortion correction is shown to be effective and clinically relevant in presurgical planning at 7T.

Peripheral Nervous System Reconstruction Reroutes Cortical Motor Output-Brain Reorganization Uncovered by Effective Connectivity.

Cortical reorganization in response to peripheral nervous system damage is only poorly understood. In patients with complete brachial plexus avulsion and subsequent reconnection of the end of the musculocutaneous nerve to the side of a phrenic nerve, reorganization leads to a doubled arm representation in the primary motor cortex. Despite, homuncular organization being one of the most fundamental principles of the human brain, movements of the affected arm now activate 2 loci: the completely denervated arm representation and the diaphragm representation. Here, we investigate the details behind this peripherally triggered reorganization, which happens in healthy brains. fMRI effective connectivity changes within the motor network were compared between a group of patients and age matched healthy controls at 7 Tesla (6 patients and 12 healthy controls). Results show the establishment of a driving input of the denervated arm area to the diaphragm area which is now responsible for arm movements. The findings extend current knowledge about neuroplasticity in primary motor cortex: a denervated motor area may drive an auxilliary area to reroute its motor output.

Early dysfunctions of fronto-parietal praxis networks in Parkinson's disease.

In Parkinson's disease (PD) the prevalence of apraxia increases with disease severity implying that patients in early stages may already have subclinical deficits. The aim of this exploratory fMRI study was to investigate if subclinical aberrations of the praxis network are already present in patients with early PD. In previous functional imaging literature only data on basal motor functions in PD exists. Thirteen patients with mild parkinsonian symptoms and without clinically diagnosed apraxia and 14 healthy controls entered this study. During fMRI participants performed a pantomime task in which they imitated the use of visually presented objects. Patients were measured ON and OFF dopaminergic therapy to evaluate a potential medication effect on praxis abilities and related brain functions. Although none of the patients was apraxic according to De Renzi ideomotor scores (range 62-72), patients OFF showed significantly lower praxis scores than controls. Patients exhibited significant hyperactivation in left fronto-parietal core areas of the praxis network. Frontal activations were clearly dominant in patients and were correlated with lower individual praxis scores. We conclude that early PD patients already show characteristic signs of praxis network dysfunctions and rely on specific hyperactivations to avoid clinically evident apraxic symptoms. Subclinical apraxic deficits were shown to correlate with an activation shift from left parietal to left frontal areas implying a prospective individual imaging marker for incipient apraxia.

Finger dexterity deficits in Parkinson's disease and somatosensory cortical dysfunction.

INTRODUCTION: The patho-physiological basis for finger dexterity deficits in Parkinson's disease (PD) is controversial. Previously, bradykinesia was regarded as the major mechanism. However, recent research suggested limb-kinetic apraxia as an important component of impaired fine motor skills in PD. In contrast to bradykinesia, limb-kinetic apraxia only marginally responds to dopaminergic treatment. Here we investigate the novel hypothesis that the dexterity deficits are related to an intrinsic dysfunction of primary somatosensory cortex (S1), which is not reversible by dopaminergic medication. METHODS: Applying a standard and approved dexterity task (coin rotation), brain activation networks were investigated using functional magnetic resonance imaging in PD patients both ON and OFF medication and matched healthy controls. RESULTS: PD patients both ON and OFF medication showed impaired S1 activation relative to controls (p < 0.05; region of interest based analysis). The impaired S1 activation remained unchanged by dopaminergic medication. Despite the considerable clinical deficit, no other brain area showed impaired activation. In contrast, structures of the basal ganglia--motor cortex loop responded to dopaminergic medication. Behaviorally, dexterity performance both ON and OFF was significantly (p < 0.05) reduced relative to controls. CONCLUSIONS: Our results provide first evidence that dexterity deficits in PD are related to an S1 dysfunction which is insensitive to dopaminergic treatment.

Comparing the Microvascular Specificity of the 3- and 7-T BOLD Response Using ICA and Susceptibility-Weighted Imaging.

In functional MRI it is desirable for the blood-oxygenation level dependent (BOLD) signal to be localized to the tissue containing activated neurons rather than the veins draining that tissue. This study addresses the dependence of the specificity of the BOLD signal - the relative contribution of the BOLD signal arising from tissue compared to venous vessels - on magnetic field strength. To date, studies of specificity have been based on models or indirect measures of BOLD sensitivity such as signal to noise ratio and relaxation rates, and assessment has been made in isolated vein and tissue voxels. The consensus has been that ultra-high field systems not only significantly increase BOLD sensitivity but also specificity, that is, there is a proportionately reduced signal contribution from draining veins. Specificity was not quantified in prior studies, however, due to the difficulty of establishing a reliable network of veins in the activated volume. In this study we use a map of venous vessel networks extracted from 7 T high resolution Susceptibility-Weighted Images to quantify the relative contributions of micro- and macro-vasculature to functional MRI results obtained at 3 and 7 T. High resolution measurements made here minimize the contribution of physiological noise and Independent Component Analysis (ICA) is used to separate activation from technical, physiological, and motion artifacts. ICA also avoids the possibility of timing-dependent bias from different micro- and macro-vasculature responses. We find a significant increase in the number of activated voxels at 7 T in both the veins and the microvasculature - a BOLD sensitivity increase - with the increase in the microvasculature being higher. However, the small increase in sensitivity at 7 T was not significant. For the experimental conditions of this study, our findings do not support the hypothesis of an increased specificity of the BOLD response at ultra-high field.