DEVICES AND METHODS FOR USING MECHANICAL AFFECTIVE TOUCH THERAPY TO REDUCE STRESS, ANXIETY AND DEPRESSION

Abstract

Methods and devices that reduce stress, anxiety and/or depression in a human using mechanical affective touch therapy is provided. In on embodiment, the method comprises (1) generating mechanical vibrations using a sinusoidal waveform and a mechanical transducer of a transcutaneous mechanical stimulation device in response to an applied electronic drive signal, (2) controlling the mechanical vibrations of the electronic drive signal by a controller board so that the mechanical vibrations have a frequency of less than 20 Hz; and (3) delivering the mechanical vibrations to the body of the human via the mechanical stimulation device, thereby providing the human with transcutaneous mechanical stimulation that reduces the human's anxiety, stress and/or depression.

Claims

1. A device for reducing anxiety in a human, the device comprising: one or more mechanical transducers, one or more batteries, one or more sinusoidal waveforms and one or more controller boards that control at least the one or more sinusoidal waveforms output through the mechanical transducers; wherein the one or more mechanical transducers, the one or more batteries and the one or more controller boards are in communication; wherein the controller board controls sinusoidal waveform output through the one or more mechanical transducers, thereby producing mechanical vibrations for a human and wherein when the device is adapted to provide mechanical vibrations in proximity to the temporal bone of the human's head.

2. The device of claim 1, wherein the frequency of the one or more waveform is less than 20 Hz.

3. The device of claim 1, wherein the frequency of the one or more waveforms is approximately 10 Hz.

4. The device of claims 1, wherein the one or more waveforms are isocronic.

5. The device of claim 1, wherein the device delivers mechanical vibrations in proximity to the temporal bone for at least 10 minutes per day.

6. The device of claim 5, wherein the device delivers mechanical vibrations in proximity to the temporal bone at least one time per day for a period of at least 4 weeks.

7. A device for reducing depression in a human, the device comprising: one or more mechanical transducers, one or more batteries, and one or more sinusoidal waveforms and one or more controller boards that control at least the one or more sinusoidal waveforms output through the mechanical transducers; wherein the one or more mechanical transducers, the one or more batteries and the one or more controller boards are in communication; wherein the controller board controls sinusoidal waveform output through the one or more mechanical transducers, thereby producing mechanical vibrations for a human and wherein when the device is adapted to provide mechanical vibrations in proximity to the temporal bone of the human's head.

8. The device of claim 7, wherein the frequency of the one or more waveform is less than 20 Hz.

9. The device of claim 7, wherein the frequency of the one or more waveforms is approximately 10 Hz.

10. The device of claims 7, wherein the one or more waveforms are isocronic.

11. The device of claim 7, wherein the device delivers mechanical vibrations in proximity to the temporal bone for at least 20 minutes per day.

12. The device of claim 11, wherein the device delivers mechanical vibrations in proximity to the temporal bone at least 2 times per day for a period of at least 4 weeks.

13. A device for reducing stress in a human, the device comprising: one or more mechanical transducers, one or more batteries, and one or more sinusoidal waveforms and one or more controller boards that control at least the one or more sinusoidal waveforms output through the mechanical transducers; wherein the one or more mechanical transducers, the one or more batteries and the one or more controller boards are in communication; wherein the controller board controls sinusoidal waveform output through the one or more mechanical transducers, thereby producing mechanical vibrations for a human and wherein when the device is adapted to provide mechanical vibrations in proximity to the temporal bone of the human's head.

14. The device of claim 13, wherein the frequency of the one or more waveform is less than 20 Hz.

15. The device of claim 13, wherein the frequency of the one or more waveforms is approximately 10 Hz.

16. The device of claim 13, wherein the one or more waveforms are isocronic.

17. The device of claim 13, wherein the device delivers mechanical vibrations in proximity to the temporal bone for at least 20 minutes per day at least 2 times per day for a period of at least 4 weeks.

18. A method of reducing anxiety, stress or depression in a human, the method comprising: generating mechanical vibrations using a sinusoidal waveform and a mechanical transducer of a transcutaneous mechanical stimulation device in response to an applied electronic drive signal; controlling the mechanical vibrations of the electronic drive signal by a controller board so that the mechanical vibrations have a frequency of less than 20 Hz; and delivering the mechanical vibrations to the body of the human via the mechanical stimulation device, thereby providing the human with transcutaneous mechanical stimulation that reduces the human's anxiety, stress and/or depression.

19. The method of claim 18, wherein the frequency of the one or more waveforms is approximately 10 Hz.

20. The method of claim 18, wherein the one or more waveforms are isocronic.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0094] The foregoing and other objects, aspects, features, and advantages of the present disclosure will become more apparent and better understood by referring to the following description taken in conjunction with the accompanying drawings, in which:

[0095] FIG. 1 shows visual examples of some the devices used and their evolution.

[0096] FIG. 2 shows visual examples of some of the actuator types and their placement.

[0097] FIG. 3. shows examples of waveforms used in accordance with at least some embodiments of the present invention described herein.

[0098] FIG. 4. shows summary of feasibility study associated with at least one of the embodiments disclosed herein.

[0099] FIG. 5 shows summary of follow up feasibility study associated with one of the embodiments disclosed herein.

[0100] FIG. 6 shows summary of clinical data associated with at least one embodiment disclosed herein.

[0101] FIG. 7 shows a table of descriptive and clinical data for all participants.

[0102] FIG. 8 shows table of data regarding pre-treatment functional connectivity relationships associated with post-MATT symptom improvement.

[0103] FIG. 9 shows table of data regarding clusters associated with acute changes in resting-state functional connectivity after initial MATT administration.

[0104] FIG. 10 shows table of date regarding seed-to-voxel functional connectivity clusters at T1-T3 associated with % change in symptom improvement upon the end of MATT treatment.

[0105] FIG. 11 shows images of pre-treatment functional connectivity seed-to-cluster pairs associated with post-MATT symptom improvement. (A) Sagittal, Coronal, and Axial representations of the left anterior insula seed derived from Neurosynth; (B) Superior view of functional connectivity of the left anterior insula seed (as seen in A) to the left posterior supramarginal gyms (PSG) cluster (circled in yellow) negatively correlated with post-treatment PSS scores (cross-validated p<0.01); (C) Sagittal, Coronal, and Axial representations of the bilateral cingulate cortex seed derived from Neurosynth; (D) Superior view of functional connectivity of the cingulate cortex seed (as seen in C) to the left precuneus as associated with post-treatment improvement in total DASS scores (cross-validated p<0.001); (E) Superior view of the same pattern of functional connectivity as seen in D, however this is associated with post-treatment improvement in DASS Stress scores (cross-validated p<0.001). All neuroanatomical images were derived using CONN toolbox.

[0106] FIG. 12 shows images of seed-to-cluster pairs associated with acute changes in resting-state functional connectivity after initial MATT administration. (A) Sagittal, Coronal, and Axial representations of the right anterior insula seed derived from Neurosynth; (B) Positive connectivity between the right anterior insula seed (as seen in A) and the left precentral gyms (lateral view) and right mid-cingulate cortex (medial view) while controlling for baseline GAD-7 scores (cross-validated p<0.001); (C) A combined superior view of the left precentral gyms and right mid-cingulate cortex clusters while controlling for baseline GAD-7 scores. All neuroanatomical images were derived using CONN toolbox.

[0107] FIG. 13 shows images of seed-to-voxel functional connectivity clusters associated with percent change in symptom improvement after MATT treatment. (A) Sagittal, Coronal, and Axial representations of the bilateral cingulate cortex seed derived from Neurosynth; (B) Lateral view of functional connectivity between the cingulate cortex seed (as seen in A) and the left anterior supramarginal gyms (ASG) correlated with decreases in Total DASS scores after MATT completion (cross-validated p=0.05); (C) Lateral view of the same pattern of functional connectivity as seen in B, however this is correlated with decreases in DASS Depression scores after MATT completion (cross-validated p=0.06). All neuroanatomical images were derived using CONN toolbox.

[0108] FIG. 14 shows supplementary table of descriptive data for participants grouped according to functional connectivity time point analyses (i.e. T1, T1-T2, and T1-T3).

[0109] FIG. 15 shows supplementary table of descriptive data for participants grouped according to functional connectivity time point analyses (i.e. T1, T1-T2, and T1-T3).

[0110] The features and advantages of the present disclosure will become more apparent from the detailed description set forth below when taken in conjunction with the drawings, in which like reference characters identify corresponding elements throughout. In the drawings, like reference numbers generally indicate identical, functionally similar, and/or structurally similar elements.

DETAILED DESCRIPTION OF THE INVENTION

[0111] It is contemplated that systems, devices, methods, and processes of the claimed inventions described herein encompass variations and adaptations developed using information from the embodiments described herein. Adaptation and/or modification of the systems, architectures, devices, methods, and processes described herein may be performed, as contemplated by the embodiments described in this application and accompanying drawings, understanding that a person of ordinary skill in the art would know to make various modifications and adjustments to the embodiments described herein while still being covered by the claims of the present disclosure.

[0112] Throughout the description, where articles, devices, and systems are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are articles, devices, and systems of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0113] It should be understood that the order of steps or order for performing certain action is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0114] The mention herein of any publication, for example, in the Background section, is not an admission that the publication serves as prior art with respect to any of the claims presented herein. The Background section is presented for purposes of clarity and is not meant as a description of prior art with respect to any aspects of the current invention or any claim.

[0115] Anxiety disorders are the most prevalent mental health-related illnesses in the United States, affecting approximately 19.1% of adults annually [1] and 11.3% of Americans in their lifetime [1]. They are associated with severe social, occupational, and physical impairment [2, 3]; increased risk for chronic diseases including diabetes, cardiovascular disease, and asthma [1], and with engagement in maladaptive behaviors like smoking and heavy drinking [4, 5]. Anxiety disorders are also associated with greater use of disability days and decreased work productivity, placing a significant burden on the US economy and healthcare system [6].

[0116] Anxiety disorders are typically treated using a combination of psychotherapy and medication. Cognitive Behavioral Therapy (CBT) is the most frequently recommended form of psychotherapy [7]. In terms of pharmacotherapy, selective serotonin reuptake inhibitors (SSRIs) are favored over benzodiazepines [8, 9]. Combined CBT and SSRI therapy has proven clinical efficacy in treating panic disorder and generalized anxiety disorder [10, 11]. Though it is the gold standard treatment approach, this approach is not, however, universally effective. One-fifth of patients fail to complete treatment citing side effects, schedule/travel barriers, poor therapeutic alliances, and motivation as reasons for discontinuation [12]. Furthermore, even among those who complete a course of treatment, symptom improvement is inadequate in one-third of patients [12]. Given the substantial burden of under-treatment on patients and on society, there is a pressing need for novel anxiety disorder treatments.

[0117] Non-invasive peripheral nerve stimulation is one promising alternative treatment for anxiety disorders. During peripheral nerve stimulation, electrical or mechanical energy is delivered to the dermal area innervated by targeted nerves [13, 14]. Research has primarily focused on electrical stimulation methods (e.g., cranial, transcranial, and transcutaneous). Electrical stimulation reduces chronic lower back pain and acute post-surgical pain [15, 16]; initial findings indicate it also improves mood and anxiety disorder symptoms [17, 18]. Mechanical (acoustic) stimulation is comparatively understudied. Still, early studies have demonstrated ultrasound (>20 KHz) stimulates AP peripheral nerves [19, 20], whereas low-frequency acoustic stimulation (<20 KHz) of somatosensory mechanoreceptors enhances proprioception [21].

[0118] Mechanical Affective Touch Therapy (MATT) is a novel non-invasive peripheral mechanical nerve stimulation device for treatment of anxiety, stress and depression. The prototype of this wearable device resembles a commercially available MP3 player, but delivers gentle vibratory stimulation (via insulated transducers) to small areas of skin behind each ear on the temporal bone. The device is configured with an amplifier and piezoelectric elements or actuators (together, transducers) that enable a MP3 -like signal generator to deliver gentle vibrations (<20 Hz). Qualitatively, these vibrations resemble those from an electric toothbrush. It is hypothesized that higher level proprioception in response to vibratory stimulation occurs through Piezo2 ion channels during Merkel-cell mechano-transduction [22]. The resulting depolarizations subsequently drive peripheral Aβ and CT-afferent impulses to cortical somatosensory (S1 and S2) and emotion processing regions (insula and anterior cingulate cortex) [23-25]. Thus, the MATT device ameliorates anxiety, depression and stress through targeted modulation of neural circuits involved in somato-sensation and pain.

[0119] Sham-controlled MATT studies indicate active transcutaneous vagus nerve stimulation (tVNS) increases magnetic resonance imaging (MM) blood oxygen level-dependent (BOLD) activation in the insula, but BOLD decreases in the thalamus, posterior cingulate cortex, and parahippocampal gyrus [26]. These patterns have been replicated in multiple cohorts of healthy humans [27, 28]. In tVNS for depression, increases in functional connectivity between the precuneus, orbital prefrontal cortex, and select regions of the Default Mode Network (DMN) have been shown to correlate with reductions in depression symptoms [29].

[0120] The DMN is a functionally interconnected network of brain regions associated with introspection [30, 31], theory of mind [32], memory retrieval [33-35], and emotion regulation [36]. Major DMN regions include bilateral lateral and medial portions of the temporal and parietal cortex, the medial prefrontal cortex, hippocampus, and parahippocampus [37]. Clinically, the DMN is implicated in anxiety [38, 39] and mood disorders [40, 41]. For example, in anxious patients, DMN BOLD activation during emotion regulation is blunted compared to activation in healthy controls [42]. Studies measuring functional connectivity, a metric of functional cohesion between brain regions [43, 44], have also found evidence of more robust connectivity between the DMN and insula in patients with heightened anxiety [45]. As tVNS can modulate brain activity in both DMN and insula [26-29],—at least in healthy individuals—mechanical stimulation provides a treatment given the involvement of both in anxiety and pain [46, 47].

[0121] A study was done using resting-state functional connectivity (RSFC) to investigate the relationship between peripheral nerve stimulation for anxiety and cortical function. To our knowledge, this is the first study to examine non-invasive transcutaneous mechanical transduction's impact on brain connectivity. We evaluated the effects of MATT treatment on RSFC in pain and anxiety circuits in adults diagnosed with Axis I anxiety disorders participating in an open-label trial. We collected MRI data and standardized assessments of anxiety, depression, and stress across MATT's four-week course. RSFC data were collected: (1) before initial MATT stimulation (baseline), (2) immediately after baseline stimulation, and (3) after completion of the treatment course. We hypothesized that acute changes in connectivity and neural predictors of treatment response would localize to DMN. Moreover, we anticipated that changes in DMN connectivity would correspond to symptom changes across treatment.

Methods and Study Overview

[0122] All participants received and used an active MATT research prototype device over 4 weeks. After the initial two MATT sessions (one at the MRI facility and the second in the research lab), participants were directed to self-administer MATT at home, or in another naturalistic setting, for at least two 20-minute sessions daily for 4 weeks. Resting-state functional MRI and structural MRI scans were obtained to enable investigation of brain changes associated with acute and chronic MATT. The first two MRI sessions occurred during the initial exposure to MATT stimulation. MRI data from time point one (T1) were acquired immediately before stimulation with MATT; time point two (T2) data were collected immediately after 15 minutes of MATT stimulation. We also collected resting state MRI data after completion of the 4-week MATT course (time point three; T3), which enabled us to evaluate brain correlates of symptom improvement after four weeks of MATT. Self-report scales assessing severity of anxiety, depression, and stress symptoms were collected at baseline, midpoint, and study endpoint.

Participants

[0123] 35 outpatients aged 18 to 65 years old with a current diagnosis of an Axis I anxiety disorder [48] were enrolled to participate in this study. Participants were recruited from the local and Butler Hospital community, obtaining written informed consent from all study participants. Participants were required to be medication-free or on a stable regimen of psychotropic medications (i.e., not started a new medication or changed doses of ongoing medications) for 30 days prior to the baseline visit and throughout the duration of their study participation. Participants were excluded if they had been psychiatrically hospitalized or had attempted suicide within the previous 6 months, had MRI safety contraindications, or were diagnosed with significant neurological conditions or another severe medical condition that could limit compliance with study procedures. All consent and study procedures were approved and supervised by the Butler Hospital Institutional Review Board. Twenty-one of the enrolled study participants completed the baseline MRI session and at least the midpoint study visits. 17 participants completed baseline and endpoint MRI scans. FIGS. 7 and 14, including Table 1 Supplemental Table 1, show participant demographics and clinical assessment scores.

Diagnostic Assessment and Medical Review

[0124] A trained clinical research assistant conducted the Mini-International Psychiatric Interview (MINI) [49] to confirm diagnosis of an Axis I Anxiety Disorder. Medical and neurological health histories and medication regimens for all participants were obtained and reviewed. As a part of this review, participants also completed a modified version of the Adverse Symptoms Checklist [50], a checklist used to monitor side effects in psychiatric clinical trials. Participants' scalps were visually inspected to confirm the absence of significant dermatological abrasion.

Self-Report Questionnaires

[0125] Anxiety symptom severity was measured using the Generalized Anxiety Disorder 7 Item questionnaire (GAD-7) [51], which also served as the primary outcome measure. The participants' perception of stress was measured using the Perceived Stress Scale (PSS) [52]. To measure intensity of depression, participants were given the Beck Depression Inventory (BDI) [53]. Additionally, to measure negative emotional states of depression, anxiety, and stress, the Depression, Anxiety, and Stress Scale (DASS) [54] was administered. Individual scores for depression, anxiety, and stress were utilized, along with total composite scores.

MATT Administration

[0126] The MATT device delivers gentle mechanical stimulation behind each ear via small (30 mm) piezoelectric disks which are mounted on a headset. The power and signal are generated from a modified MP3 player that effectively ‘plays’ the signal that the piezos convert to vibration. Individualized optimal stimulation was assigned by determining the sub-threshold vibrational level for each participant.

[0127] The first two stimulation sessions were administered by research staff concurrently with EEG collection or at their MRI visit and then participants were instructed to self-administer MATT at home or other naturalistic settings twice a day for four weeks. Once started, the device delivers stimulation for 20 minutes. The recommended trial dosing was two sessions a day with the option to use a third time if needed (i.e., if feeling more anxious or during anxiety-provoking situations). The MATT device used in this study, the piezos were driven by a sinusoidal 10 Hz signal that was delivered isochronically, having an active period of 2 seconds followed by 2 seconds of inactivity, called the ‘refractory period’. The piezos vibrate with a displacement between 0.01 and 0.05 MM.

MRI Data Collection and Preprocessing

[0128] All brain scan procedures took place at the Brown University MRI Facility. The first two scans occurred during Study Visit 2 (MRI baseline) and the final scans during Study Visit 6 (MRI endpoint) using a Siemens 3T MRI Scanner (Erlangen, Germany) and a 64-channel head coil. During Visit 2, prior to MATT stimulation, we collected a structural T1-weighted image (TE=1.69 ms, TR=2530 ms, FOV=256 mm2, 1 mm3) and 10 minutes of resting-state functional MRI data (TE=30 ms, TR=1000 ms, FOV=192 mm2, 2 mm3, 588 volumes). During the resting scan, participants were instructed to lay still and focus their gaze on a display screen showing a white crosshair in the middle of a black foreground. This screen was positioned at the back of the scanner bore and was viewed through a small MRI-safe mirror affixed to the scanner head coil. After these initial scans, the participant was removed from the scanner and underwent their first MATT stimulation session in a separate room. Immediately after, participants returned to the scanner for additional T1-weighted structural and resting state scans. Following completion of the last MATT session and final clinical assessments (Visit 5), additional structural and functional scans were collected. MATT was not administered during this MRI session.

[0129] All MRI data preprocessing steps were executed with the CONN Toolbox [55] (https://web.conn-toolbox.org). Standard MRI preprocessing steps included slice-time correction, motion estimation and realignment, normalization of images to Montreal Neurological Institute (MNI)-152 Atlas space, and spatial smoothing with a 6 mm full-width half-max gaussian kernel. Additional functional connectivity preprocessing steps were applied to reduce the contribution of non-neuronal signals and motion on functional connectivity [56, 57]. We used the Anatomical CompCor method [58] to model non-neuronal signals: five principle components were computed from white matter and cerebrospinal fluid BOLD time-courses. These components were then regressed from subjects' preprocessed data along with six estimated motion parameters (3 translational, 3 rotational) and their first temporal derivatives, and the linear trend. Residuals were then band-pass filtered before first-level modeling.

Subject-Level Seed-To-Voxel Analyses

[0130] Functional regions-of-interest (ROI) or functional connectivity “seeds” were based on construct maps for “pain” and “anxiety” in Neurosynth (https://neurosynth.org/). Neurosynth [59] is a meta-analytic tool that generates functional connectivity maps for lexical terms and cognitive processes. To define our ROIs, each term's map using a minimum z-score and extracted clusters of spatially contiguous voxels were thresholded. Thresholding the “anxiety” map at z-scores>5 yielded two ROIs centered on the amygdala in each hemisphere. More stringent threshold (z-scores>7) for the “pain” ROIs to improve cluster separation were used. This produced bilateral clusters in the anterior insula and thalamus, and a mid-cingulate ROI crossing the sagittal midline.

[0131] For each seed, a whole-brain voxel-wise map of correlations with the seed's BOLD time-course was constructed. These subject-level maps underwent Fisher's R-to-Z transformation to improve conformation to the assumptions of generalized linear models. These seed maps were entered into second-level analyses of covariance (ANCOVA; see below) models for hypothesis testing.

Second-Level Hypothesis Testing And Cross-Validation

[0132] Second-level models were constructed to: 1) identify pre-treatment connectivity patterns predictive of subsequent treatment outcomes; 2) localize acute connectivity changes immediately after MATT; 3) ask whether acute connectivity change predicts treatment outcome, and 4) identify post-treatment correlates of symptom improvement. All model results were evaluated using an uncorrected voxel-height threshold (p<0.005) and were multiple comparisons corrected at p-FDR<0.05. A leave-one-out cross-validation analysis was performed for all significant clusters. Briefly, on each iteration, models were re-estimated leaving one subject out and a parameter estimate (beta weight) was generated for the left-out subject based on this model. To determine if a cluster cross-validated, we submitted these estimated weights to a two-tailed t-test against the mean with alpha set at p<0.05. We also excluded clusters if they were present in less than 80% of cross-validation masks. Only those results that survived leave-one-out cross-validation are presented in this disclosure.

[0133] To identify clusters predictive of treatment outcomes, continuous variables corresponding to clinical symptom scores were constructed at study endpoint (or last observation carried forward). Seed maps from the pre-treatment imaging session (timepoint one or T1) were entered into an ANCOVA model evaluating the between subjects' effect of endpoint scores after covariance for symptom severity at study baseline.

[0134] To localize acute effects of MATT, we compared pre-treatment (T1) seed maps to those collected immediately after MATT delivery (T2), evaluating within-subject change after covariance for baseline clinical symptoms. To localize brain regions where acute changes in functional connectivity were associated with subsequent improvement in clinical symptoms, we tested the between-subjects effect of post-treatment symptom change with session (T1>T2) as the within-subjects factor. Symptom change was operationalized as percent change in scale score (GAD, DASS, PSS, BDI) from baseline to endpoint, a procedure which normalizes baseline differences in symptom severity.

[0135] To identify functional correlates of clinical improvement, the significance of the between-subjects effect of symptom change on pre-treatment versus post-treatment (T1-T3) seed-to-voxel connectivity was tested.

Morphometry Analyses

[0136] Freesurfer (v.5.3; http://surfer.nmr.mgh.harvard.edu/) software was used to explore the relationship between functional connectivity changes associated with MATT response and brain structure. Subjects' structural images from the T1 and T3 sessions were preprocessed using the ‘fsrecon-all’ routine. Steps included: skull stripping, volumetric labeling, intensity normalization, tissue parcellation, registration to Freesurfer's default spherical atlas (‘fsaverage’), surface extraction, cortical labeling. For complete technical details of Freesurfer preprocessing, see [60-66]. We examined cortical thickness in the insula and mid-cingulate, as defined in [67], and subcortical volumes in MNI space in the left thalamus and amygdala. Metrics were calculated and extracted by Freesurfer. Volume estimates were adjusted to account for differences in brain volume. We then used SPSS (IBM; v25) to compute correlations between subject-level morphometry values and beta coefficients from the analysis of functional connectivity changes post-MATT. Statistical significance was evaluated at a one-tailed p<0.05.

Results

Predictors of Treatment Outcomes

[0137] We found that stronger positive connectivity between pain and anxiety regions to the DMN, was generally predictive of greater clinical improvement at treatment endpoint. Functional connectivity of the left amygdala to DMN clusters in both the right and left lateral temporal cortex were negatively correlated with post-treatment GAD scores (both cross-validated p<0.005). Similarly, functional connectivity of left anterior insula to left posterior supramarginal gyms was also negatively correlated with post-treatment PSS scores (cross-validated p<0.01; see FIG. 1), though this part of parietal cortex is implicated in executive control networks, rather than DMN. Stronger positive connectivity between the cingulate pain ROI and the left precuneus (DMN) was also associated with post-treatment improvement in total DASS scores (cross-validated p<0.001). Closer examination of DASS by subscale indicated that this relationship was driven by the stress dimension (See FIG. 11). All findings remained significant after covariance for symptom severity at baseline and percent completed MATT sessions. See FIG. 8, Table 2 for additional cluster information.

Acute Changes in Functional Connectivity

[0138] We observed increases in right anterior insula functional connectivity immediately after the initial session of MATT stimulation (See FIG. 9 Table 3). Weak positive connectivity between the right insula seed and right middle cingulate cortex and left precentral gyrus observed at baseline became stronger after MATT (cross-validated p<0.001; See FIG. 12). Prior to stimulation, right insula and left precentral time courses were anti-correlated but became positively correlated after stimulation (cross-validated p<0.005). Post hoc tests indicated that these connectivity relationships remained significant when baseline clinical symptoms were included as model covariates (GAD, BDI, PSS, DASS Total, DASS Stress, DASS Anxiety, and DASS Depression).

Functional Connectivity and Post-Treatment Symptom Change

[0139] Increases in positive functional connectivity between the cingulate cortex and the left anterior supramarginal cortex after MATT completion were correlated with decreases in total DASS scores (cross-validated p=0.05). Additional testing conducted within DASS subscales indicated that this connectivity relationship was associated with changes in depression (cross-validated p<0.05) and stress (cross-validated p=.06), but not with changes in reported anxiety (see Table 4 and FIG. 3).

Exploratory Structure-Function Correlations

[0140] Our morphometry results preliminarily indicate that cortical thickness within pain circuits influences functional responsiveness to MATT. At baseline, greater cortical thickness in the right insula was associated with connectivity correlates of total DASS (r(14)=−0.40, p=0.08) and DASS depression (r(14)=−0.48, p<0.05) reductions post-MATT. Similar correlations were also observed in the left cingulate for total DASS (r(14)=−0.41, p=0.07) and DASS depression (r(14)=−0.51, p<0.05). We next computed percent change in cortical thickness across sessions T1 and T3 and correlated these against our connectivity change coefficients. While the relationship between changes in thickness and connectivity were marginally significant in the right insula (DASS total: r(14)=0.42, p=0.07; DASS depression: r(14)=0.43, p=0.06), correlations for the left cingulate were not significant (all p>0.2).

[0141] The experiments described herein examined the relationship between changes in mood and anxiety symptoms and functional brain connectivity in individuals receiving peripheral nerve stimulation with the MATT device. The inventions described herein using MATT are the first acoustic, non-invasive mechanical stimulation device designed to treat anxiety, stress and depression. We also examined transcutaneous mechanical stimulation-induced changes in brain connectivity in patients with anxiety disorders. Broadly, our results indicate that MATT is capable of acute modulation of pain and anxiety networks and that modulation of connectivity between pain processing and internal mentation networks may be a key component of mechanical stimulation response.

[0142] As hypothesized, more robust pre-treatment functional connectivity between pain and anxiety regions, and the DMN predicted superior treatment response. Previous studies found that stronger connectivity between these networks is associated with anxiety severity [45, 68, 69]. In this study, we found that stronger inter-network connectivity predicted superior reduction in anxiety and stress symptoms. Specifically, stronger connectivity between the amygdala (“anxiety” seed) and the lateral temporal cortex at baseline was linked to greater anxiety reduction at the end of MATT. Similarly, stronger functional connectivity between the insula (“pain” seed) and the precuneus (DMN) was associated with larger decreases in stress. While DMN regions generally contribute to internally focused cognition, functional fractionations of this network link lateral temporal DMN to social cognition, and midsagittal DMN to affect and memory [70]. We speculate that stronger connectivity between anxiety regions and the DMN may facilitate safety learning through increased cross-network functional integration [71, 72].

[0143] In contrast to our a priori expectations, and observations from tVNS [26], we did not observe functional connectivity changes between pain and anxiety networks to DMN after initial MATT administration. Instead, we observed increases in insula connectivity to pain and motor regions including the mid-cingulate and postcentral cortex. Though the insula is associated with pain [73], it is also part of a broader network inclusive of midcingulate [74, 75] and postcentral cortex [76] involved in salience monitoring [77] and embodied sensation [78, 79]. We surmise that the observed pattern of acute connectivity increases could reflect the engagement of salience or haptic/pain monitoring in response to MATT stimulation.

[0144] Finally, we observed the anticipated correlation of changes in connectivity and symptoms post-treatment for pain seeds. Increases in mid-cingulate connectivity with the lateral subnetwork of the DMN were correlated with post-treatment reductions in depression and stress domain scores on the DASS. This prediction, however, did not hold for our anxiety seeds. This null finding may reflect our use of a naturalistic sample and stricter inclusion criteria for anxiety versus other clinical symptoms. Alternatively, our results may indicate that the latency to response differs between clinical symptoms or that MATT modifies different networks across the treatment course. To wit, we observed changes in pain network connectivity to salience and interoception regions acutely, whereas post-treatment pain connectivity effects localized to DMN. Our preliminary structural results also highlight the centrality of pain and salience circuits to MATT response.

Limitations

[0145] Several limitations of the experiments disclosed herein must be noted. First, this preliminary study used an open-label design without a sham control condition. Though promising, it remains to be seen if results will replicate in a blinded, randomized control trial (RCT). We also note that our sample size was small, and despite cross-validations, these imaging results should be regarded as preliminary until replicated by a larger sample RCT. In addition, our primary measure of anxiety, the GAD-7, had fewer questions and thus less variability than our measures of depression and stress, potentially leading to more non-significant findings in relation to anxiety symptoms. Finally, though we speculate that our findings are suggestive of an underlying temporal heterogeneity in the response of brain networks to MATT, we acknowledge that the evaluation of functional connectivity at rest, rather than on task may introduce network bias.

Conclusion

[0146] In summary, MATT is a novel treatment to alleviate and reduced anxiety, stress and depression in a human after altering resting state functional connectivity in the DMN after both acute and long-term administration. Analyses revealed that MATT-induced increased connectivity between pain and anxiety ROIs and the posterior DMN correlate with decreases in anxiety, stress and depression. This study is an important first step in developing non-invasive alternative anxiety treatments that alleviate symptoms through alteration of brain connectivity.

References

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