Delta wave magnetic resonance imaging (MRI) and methods of use thereof

Abstract

The present invention relates to the fields of measuring brain activity and detecting and diagnosing a brain pathology. Methods for monitoring and / or indexing a subject's sleep or sleep patterns are also provided. Methods for determining the efficacy of therapy against a brain pathology are also provided. In certain embodiments, the method comprises performing a fast BOLD sensitive MRI. In certain embodiments, the method comprises performing an ultrafast magnetic resonance (MR) encephalography (MREG) on the subject and detecting an alteration in brain activity

Description

[0001] DELTA WAVE MAGNETIC RESONANCE IMAGING (MRI) AND METHODS OF USE THEREOF

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 602,574, filed November 25, 2023. The foregoing application is incorporated by reference herein.

[0003] This invention was made with government support under Grant No. R01 MH129594 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to the fields of measuring brain activity and detecting and diagnosing a brain pathology.

[0006] BACKGROUND OF THE INVENTION

[0007] Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.

[0008] Conventional functional magnetic resonance imaging (fMRI) is not used for directly measuring brain electrophysiology because of relatively low (-sees) temporal resolution and a lack of signal sensitivity to the electromagnetic fields that arise directly from neuronal electrical current activity. Traditionally, other modalities such as electroencephalography (EEG) and magnetoencephalography (MEG) have provided direct measures of brain electric potentials and magnetic fields with sufficient temporal resolution to detect functionally-relevant neural oscillations ranging from delta (~l-4 Hz) to gamma (>30 Hz) bands. However, EEG and MEG lack the spatial resolution and precise source localization (i.e., image formation) intrinsic to MRI techniques such as blood oxygen level dependent (BOLD) fMRI, as well as requiring dedicated hardware and scanning sessions that need to be subsequently augmented by a separate anatomic MRI for visualization of source estimates. Accordingly, new, superior methods for detection and observation of endogenous slow brain activity (delta band) are needed.

[0009] SUMMARY OF THE INVENTION

[0010] In accordance with the instant invention, methods for measuring brain activity and / or detecting or diagnosing a brain pathology in a subject are provided. Methods for monitoring and / or indexing a subject’s sleep or sleep patterns are also provided. Methods for determining the efficacy of therapy against a brain pathology are also provided. In certain embodiments, the method comprises performing a fast BOLD- sensitive MRI. In certain embodiments, the method comprises performing an ultrafast magnetic resonance (MR) encephalography (MREG) on the subject and detecting an alteration in brain activity. In certain embodiments, the ultrafast MREG is at least about 10 frames per second. In certain embodiments, the brain activity is limited to a defined range of frequencies or frequency band (e.g., theta, alpha, beta, delta, or gamma, particularly delta waves). In certain embodiments, the brain activity is that with brain waves less than approximately 4 Hz (e.g., about 0.1 Hz to 4.0 Hz). In certain embodiments, the alteration of brain activity in the subject is indicative of the brain pathology. In certain embodiments, the method comprises comparing the brain activity in the subject with a reference from a healthy control; comparing the brain activity in the subject with a reference from a subject with a brain pathology; and / or comparing the brain activity in the subject with the brain activity of the subject prior to a purported brain pathology inducing event (e.g., a traumatic brain injury). In certain embodiments, the method further comprises diagnosing the subject with a brain pathology based on the detected alteration in brain activity. In certain embodiments, the method further comprises administering a therapy and / or a therapeutic agent to the subject for treatment of the brain pathology. In certain embodiments, the brain pathology is a traumatic brain injury. In certain embodiments, the brain pathology is a concussion.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figures 1 A and IB provide a schematic of a simulation of the post processing procedure. Figure 1 A: The delta band activity (top) was convolved with a hemodynamic response function modeled (middle) to produce a signal simulating the BOLD contrast sampled by the MREG signal (bottom). Figure IB: The spectral activity of a voxel and timepoint is provided (top) which can be deconvolved with the hemodynamic response to provide the original brain wave activity (bottom).

[0013] Figure 2A provides an MREG timecourse of single voxel from the frontal cortex. The approximate time period of sleep is indicated by the horizontal arrow. The vertical arrow indicates the known timepoint when the subject was woken up. The timecourse amplitude is noticeably higher during the period of sleep. Figure 2B provides the corresponding spectrogram showing the full temporal-spectral data for a single voxel. The delta-band sleep power is elevated. Figure 2C provides the temporal evolution of the slow wave power which is computed by integrating over the specified frequency rows in the spectrogram of Figure 2B.

[0014] Figure 3 provides an overview of a MR slow wave detection method using MREG. MREG reconstruction is performed as a post-processing step prior to timecourse, spectral, and spectrogram computations. The spectral power of each voxel in the brain may be visualized as an image, a “delta wave MRI.”

[0015] Figure 4 provides the spatial distribution of delta power visualized across the brain during the initial awake period, the sleep period, and the final awake period. Full delta band power between 0.2 and 5 Hz was averaged over a 50 s period for every voxel in the brain and is expressed in arbitrary units related to MREG BOLD signal intensity. Delta power is highest during sleep and is generally strongest in brain periphery and sulcal regions, consistent with cortical tissue.

[0016] Figure 5A provides a voxel-wise t-map showing brain regions with increased slow wave (0.2-5 Hz) MREG activity during sleep. The t-map is derived from an fMRI-style student t-test with an asymmetric box-car of 250 s awake, 500 s asleep and 250 s awake. Figure 5B provides an MREG timecourse of single voxel from the right temporal cortex which was selected to demonstrate the spectral-temporal data may be computed and visualized. The MREG BOLD signal timecourse is displayed after filtering out ultra-low frequencies. The approximate time period of sleep is indicated by the horizontal arrow. The vertical arrow indicates the known timepoint when the subject was woken up. The timecourse amplitude is noticeably higher during the period of sleep. Figure 5C provides the corresponding spectrogram showing the full temporal-spectral data for a single voxel. The delta-band sleep power is elevated. Figure 5D provides the temporal evolution of the slow wave power which is computed by integrating over the specified frequency rows in the spectrogram of Figure 5C. DETAILED DESCRIPTION OF THE INVENTION

[0017] A novel application of MR encephalography (MREG) to detect the frequency spectrum of endogenous slow oscillatory brain activity (delta, <4 Hz) is provided. MREG offers faster image acquisition than conventional fMRI and superior spatial localization than EEG / MEG. MREG was acquired at 0.1 sec temporal resolution in a healthy adult during wakefulness and sleep to demonstrate its capability for detecting delta-band power changes associated with sleep (Dang-Vu, et al. (2008) Proc. Natl. Acad. Sci., 105(39): 15160-15165). For each voxel (3D pixel), the brain activity MREG signal was used to compute a spectrogram and whole brain image of deltaband spectral power. Delta-band power was observed to increase during sleep as compared to awake states using measures from MREG voxel -wise spectrograms and whole brain spatial maps of slow wave power. Accordingly, an MR technique for measuring brain slow wave activity which is sensitive to changes in the magnitude and frequency of brain activity, such as in sleep, has been provided.

[0018] Herein, it is demonstrated that combining ultrafast magnetic resonance (MR) encephalography (MREG) functional magnetic resonance imaging (fMRI) acquisition with spectrally selective filtering allows for the detection and localization of selected electrophysiological brain activity within specific frequency bands. Specifically, the feasibility of selecting - and thus imaging - power only in the delta frequency band has been demonstrated, as an exemplar of more general frequency-selective power mapping. Spatial foci and temporal dynamics can be probed, revealing in this demonstration the timecourse of wakefulness, drowsiness, and sleep. Since delta waves (~l-4Hz) can be associated with pathologic brain activity of the awake brain in traumatic brain injury (e.g., mild traumatic brain injury or concussion), Alzheimer dementia, tumor, stroke, epilepsy and other neurologic conditions, as well as indexing sleep (as demonstrated here), the instant invention can be used for such applications and will yield both spatial localization of pathologic neural oscillatory activity as well as spectral features and temporal dynamics.

[0019] By using ultrafast MRI, one is able to increase the spectral width (bandwidth) to approximately 5Hz. This is known as MR encephalography, which is primarily used as a precursor to elimination of unwanted signals in this frequency range like respiratory or cardiac artifacts. On the other hand, it is known from magnetoencephalography (MEG) that focal slow- wave (1-4 Hz, also known as the delta band) activity is a hallmark of mild traumatic brain injury or concussion. Herein, these two concepts are fused by incorporating the speed of MR encephalography (approx. 10 frames per second or more) with a band-pass filter (e.g., 1-4 Hz) to eliminate low frequency fluctuations and directly observe activity only in the delta band. With this approach, 3D MR images can be made with a signal intensity which is elevated in regions of traumatic brain injury. This will have use in diagnosis and monitoring rehabilitation as a non-invasive, objective marker.

[0020] The brain spectral MR technique of the instant invention has applications to brain conditions, diseases, and developmental abnormalities which alter brain activity. Patients with Alzheimer’s, concussion and brain injury have been shown with EEG and MEG to exhibit “slowing” of brain activity associated with an increase in delta band activity. This technique is sensitive to changes in the magnitude of brain spectral activity, including delta band activity. The technique of delta wave MRI (or more broadly “frequency selective brainwave MRI”) will be efficacious in diagnosis, prognosis and monitoring therapeutic interventions in such neurologic conditions.

[0021] Without being bound by theory, the convolution property states that: wherein x(t) = comb of delta functions at interval 4secs, h(t) = HRF (Gamma variate + 1stderivative), and observed signal on MREG is the convolution of x(t) and h(t), call it y(t).

[0022] To start, let

[0023] Then, the Fourier Transform of j (Z) can be plugged in the convolution integral for y(f).

[0024] The integrals have been marked with dt and dr to keep track of them.

[0025] Now, the order of the two integrals is switched: let u = t - T

[0026] Therefore,

[0027] Thus, the FT of the signal is the product of the FT of the HRF and the FT of the electrophysiological driving function (0.25Hz sinc / peak).

[0028] The Fourier Transform of the convolution of two functions is simply the product of the Fourier Transforms of the functions. This means that for linear, timeinvariant systems, where the input / output relationship is described by a convolution, convolution can be avoided by using Fourier Transforms.

[0029] However, in many circumstances, it may be that the need for deconvolution of the HRF is obviated by the brain’s natural physiologic response (Polimeni, et al. (2021) Prog. Neurobiol., 207: 102174) in the setting of near-continuous, ongoing, low- amplitude electrophysiological rhythms. The instant invention will nonetheless be sensitive to, and reveal, delta wave activity in these settings too.

[0030] In accordance with the instant invention, methods of measuring brain activity are provided. In accordance with the instant invention, methods of detecting and / or diagnosing a brain pathology (e.g., a structural and / or functional deviation from normal) are also provided. In certain embodiments, the brain pathology is a condition or disease. In certain embodiments, the brain pathology is a developmental abnormality. In certain embodiments, the brain pathology is a brain injury, particularly a traumatic brain injury such as a mild traumatic brain injury or a concussion. In certain embodiments, the brain pathology is Alzheimer’s disease. In certain embodiments, the brain pathology is dementia. In certain embodiments, the brain pathology is epilepsy or other neurologic condition. In certain embodiments, the brain pathology is Parkinson’s disease. In certain embodiments, the brain pathology is a tumor (e.g., brain tumor). In certain embodiments, the brain pathology is a stroke. In certain embodiments, the brain pathology is a cerebral edema. In certain embodiments, the brain pathology is a sleep disorder. The methods of the instant invention can also be used to monitor and / or index sleep.

[0031] As used herein, a “traumatic brain injury” or “TBI” refers to an acquired brain injury or a head injury, when a trauma causes damage to the brain. Trauma includes, without limitation, post-head trauma, impact trauma, and other traumas to the head such as, for example, traumas caused by accidents and / or sports injuries, traumas incurred on the battlefield (e.g., explosions, bombs, explosive devices, etc.), concussive injuries, and the like. In certain embodiments, the trauma is an external, physical force or blow, particularly to the head. In certain embodiments, the traumatic brain injury is a mild traumatic brain injury. In certain embodiments, the traumatic brain injury is a concussion.

[0032] The injury or damage to the brain can be focal (confined to one area of the brain) or diffuse (involving more than one area of the brain). In certain embodiments, the traumatic brain injury can result from a closed head injury. Clinically, traumatic brain injury can be rated as mild, moderate or severe based on TBI variables that include duration of loss of consciousness (LOC), Glasgow Coma Score (GCS; e.g., mild 13-15; moderate = 9-12; severe = <8) and post traumatic amnesia. In certain embodiments, the TBI detected and / or diagnosed by the instant invention is mild or moderate, particularly mild.

[0033] In certain embodiments, the traumatic brain injury can be repetitive, where the brain is subject to repeated physical loading to the brain. Generally, repetitive traumatic brain injury is typically a mild to moderate form of closed brain injury repeatedly suffered by a subject (e.g., athlete (e.g., football player), soldier, etc.), resulting in increased incidence of impaired motor, cognitive, and / or behavioral impairments months to years following the traumatic brain injuring events.

[0034] In certain embodiments, the methods of the instant invention (e.g., measuring brain activity and / or detecting and / or diagnosing a brain pathology) comprise i) performing an ultrafast, blood oxygen level dependent (BOLD)-sensitive MRI or an ultrafast magnetic resonance (MR) encephalography (MREG) on the subject (e.g., by functional magnetic resonance imaging (fMRI) or BOLD fMRI), wherein the ultrafast MREG is at least 10 frames per second, and ii) detecting an alteration (e.g., increase) in brain activity. In certain embodiments, the subject is in a resting state. In certain embodiments, the detection of brain activity is limited to a defined frequency band (e.g., theta, alpha, beta, delta, or gamma, particularly delta waves). In certain embodiments, the detection of brain activity is limited to brain waves less than approximately 4 Hz, particularly about 0.1 Hz to about 4.0 Hz, about 0.2 Hz to about 4.0 Hz, or about 1.0 Hz to about 4.0 Hz). In certain embodiments, the detection of brain activity is across the whole brain. In certain embodiments, the detection of brain activity is limited to a certain area or region (e.g., temporal cortex or right temporal cortex) of the brain (e.g., an area or region of the brain pathology (e.g., site of trauma or disease)). In certain embodiments, the detection of brain activity is limited to certain voxels.

[0035] The alteration in brain activity may be in comparison to a reference from a healthy control; comparison to a reference from a subject with a brain pathology (e.g., the brain pathology to be detected and / or diagnosed); and / or in comparison to the subject prior to an event (e.g., a brain injury). In certain embodiments, the method further comprises diagnosing the subject with a brain pathology based on the detected alteration in brain activity. For example, a change in the subject’s brain activity to the brain activity observed in a reference with a brain pathology indicated the presence of the brain pathology. As another example, a change (e.g., increase) in the subject’s brain activity compared to the subject’s baseline or a healthy control indicates the presence of the brain pathology.

[0036] In certain embodiments, the methods of the instant invention (e.g., measuring brain activity and / or detecting and / or diagnosing a brain pathology) comprise i) performing an ultrafast BOLD-sensitive MRI or an ultrafast magnetic resonance (MR) encephalography (MREG) on the subject (e.g., by functional magnetic resonance imaging (fMRI) or BOLD fMRI), wherein the ultrafast MREG is at least 10 frames per second, ii) creating a 4D (x,y,z,time) image volume, and iii) detecting an alteration in brain activity. In certain embodiments, the subject is in a resting state. In certain embodiments, the detection of brain activity is limited to a defined frequency band (e.g., theta, alpha, beta, delta, or gamma, particularly delta waves). In certain embodiments, the detection of brain activity is limited to brain waves less than approximately 4 Hz, particularly about 0.1 Hz to about 4.0 Hz, about 0.2 Hz to about 4.0 Hz, or about 1.0 Hz to about 4.0 Hz). In certain embodiments, the detection of brain activity is across the whole brain. In certain embodiments, the detection of brain activity is limited to a certain area or region (e.g., temporal cortex or right temporal cortex) of the brain (e.g., an area or region of the brain pathology (e.g., site of trauma or disease)). In certain embodiments, the detection of brain activity is limited to certain voxels.

[0037] The alteration in brain activity may be in comparison to a reference from a healthy control; comparison to a reference from a subject with a brain pathology (e.g., the brain pathology to be detected and / or diagnosed); and / or in comparison to the subject prior to an event (e.g., a brain injury). In certain embodiments, the method further comprises diagnosing the subject with a brain pathology based on the detected alteration in brain activity. For example, a change in the subject’s brain activity to the brain activity observed in a reference with a brain pathology indicated the presence of the brain pathology. As another example, a change (e.g., increase) in the subject’s brain activity compared to the subject’s baseline or a healthy control indicates the presence of the brain pathology.

[0038] In certain embodiments, the methods of the instant invention (e.g., measuring brain activity and / or detecting and / or diagnosing a brain pathology) comprise i) performing an ultrafast BOLD-sensitive MRI or an ultrafast magnetic resonance (MR) encephalography (MREG) on the subject (e.g., by functional magnetic resonance imaging (fMRI) or BOLD fMRI), wherein the ultrafast MREG is at least 10 frames per second, ii) extracting a brain activity timecourse, and iii) detecting an alteration in brain activity. In certain embodiments, the subject is in a resting state. In certain embodiments, the detection of brain activity is limited to a defined frequency band (e.g., theta, alpha, beta, delta, or gamma, particularly delta waves). In certain embodiments, the detection of brain activity is limited to brain waves less than approximately 4 Hz, particularly about 0.1 Hz to about 4.0 Hz, about 0.2 Hz to about 4.0 Hz, or about 1.0 Hz to about 4.0 Hz). In certain embodiments, the detection of brain activity is across the whole brain. In certain embodiments, the detection of brain activity is limited to a certain area or region (e.g., temporal cortex or right temporal cortex) of the brain (e.g., an area or region of the brain pathology (e.g., site of trauma or disease)). In certain embodiments, the detection of brain activity is limited to certain voxels.

[0039] The alteration in brain activity may be in comparison to a reference from a healthy control; comparison to a reference from a subject with a brain pathology (e.g., the brain pathology to be detected and / or diagnosed); and / or in comparison to the subject prior to an event (e.g., a brain injury). In certain embodiments, the method further comprises diagnosing the subject with a brain pathology based on the detected alteration in brain activity. For example, a change in the subject’s brain activity to the brain activity observed in a reference with a brain pathology indicated the presence of the brain pathology. As another example, a change (e.g., increase) in the subject’s brain activity compared to the subject’s baseline or a healthy control indicates the presence of the brain pathology.

[0040] In certain embodiments, the methods of the instant invention (e.g., measuring brain activity and / or detecting and / or diagnosing a brain pathology) comprise i) performing an ultrafast BOLD-sensitive MRI or an ultrafast magnetic resonance (MR) encephalography (MREG) on the subject (e.g., by functional magnetic resonance imaging (fMRI) or BOLD fMRI), wherein the ultrafast MREG is at least 10 frames per second; ii) creating a 4D (x,y,z,time) image volume; iii) extracting a brain activity timecourse (e.g., at each voxel); iv) constructing a spectrogram of brain activity (e.g., a voxel-wise temporal variation of spectral power); v) constructing a spatial map of spectral power; and vi) detecting an alteration in brain activity. In certain embodiments, the subject is in a resting state. In certain embodiments, the detection of brain activity is limited to a defined frequency band (e.g., theta, alpha, beta, delta, or gamma, particularly delta waves). In certain embodiments, the detection of brain activity is limited to brain waves less than approximately 4 Hz, particularly about 0.1 Hz to about 4.0 Hz, about 0.2 Hz to about 4.0 Hz, or about 1.0 Hz to about 4.0 Hz). In certain embodiments, the detection of brain activity is across the whole brain. In certain embodiments, the detection of brain activity is limited to a certain area or region (e.g., temporal cortex or right temporal cortex) of the brain (e.g., an area or region of the brain pathology (e.g., site of trauma or disease)). In certain embodiments, the detection of brain activity is limited to certain voxels.

[0041] The alteration in brain activity may be in comparison to a reference from a healthy control; comparison to a reference from a subject with a brain pathology (e.g., the brain pathology to be detected and / or diagnosed); and / or in comparison to the subject prior to an event (e.g., a brain injury). In certain embodiments, the method further comprises diagnosing the subject with a brain pathology based on the detected alteration in brain activity. For example, a change in the subject’s brain activity to the brain activity observed in a reference with a brain pathology indicated the presence of the brain pathology. As another example, a change (e.g., increase) in the subject’s brain activity compared to the subject’s baseline or a healthy control indicates the presence of the brain pathology. In certain embodiments, the methods of the instant invention (e.g., measuring brain activity and / or detecting and / or diagnosing a brain pathology) comprise i) performing an ultrafast BOLD-sensitive MRI or an ultrafast magnetic resonance (MR) encephalography (MREG) on the subject (e.g., by functional magnetic resonance imaging (fMRI) or BOLD fMRI), wherein the ultrafast MREG is at least 10 frames per second; ii) creating a 4D (x,y,z,time) image volume; iii) extracting a brain activity timecourse; iv) performing a fourier transformation of the brain activity timecourse; v) deconvoluting the hemodynamic response function (HRF); vi) constructing a spectrogram of brain activity; vii) constructing a spatial map of spectral activity; and viii) detecting an alteration in brain activity. In certain embodiments, the subject is in a resting state. In certain embodiments, the detection of brain activity is limited to a defined frequency band (e.g., theta, alpha, beta, delta, or gamma, particularly delta waves). In certain embodiments, the detection of brain activity is limited to brain waves less than approximately 4 Hz, particularly about 0.1 Hz to about 4.0 Hz, about 0.2 Hz to about 4.0 Hz, or about 1.0 Hz to about 4.0 Hz). In certain embodiments, the detection of brain activity is across the whole brain. In certain embodiments, the detection of brain activity is limited to a certain area or region (e.g., temporal cortex or right temporal cortex) of the brain (e.g., an area or region of the brain pathology (e.g., site of trauma or disease)). In certain embodiments, the detection of brain activity is limited to certain voxels.

[0042] The alteration in brain activity may be in comparison to a reference from a healthy control; comparison to a reference from a subject with a brain pathology (e.g., the brain pathology to be detected and / or diagnosed); and / or in comparison to the subject prior to an event (e.g., a brain injury). In certain embodiments, the method further comprises diagnosing the subject with a brain pathology based on the detected alteration in brain activity. For example, a change in the subject’s brain activity to the brain activity observed in a reference with a brain pathology indicated the presence of the brain pathology. As another example, a change (e.g., increase) in the subject’s brain activity compared to the subject’s baseline or a healthy control indicates the presence of the brain pathology.

[0043] In certain embodiments, the methods of the instant invention comprise one or more (e.g., all) of the following steps:

[0044] 1. MRI Scan: Ultrafast BOLD-sensitive MRI or ultra-fast (10 frames / second or greater) MR encephalography (MREG) is sensitive to the brain’s blood oxygen levels at sampling rates fast enough to measure brain wave activity in frequencies typically the domain of electrophysiology (EEG or MEEG). The subject may undergo the MRI or MREG exam under resting state conditions.

[0045] 2. Image Volume Reconstruction: The images from the scan are reconstructed to create a 4D (x,y,z,time) image volume.

[0046] 3. Extraction of Brain Activity Timecourse: Brain activity during the scan causes hemodynamic responses and changes in the brain’s blood oxygen levels. Variations over time and space in the reconstructed images volume intensity are related to spatial and temporal variations in brain activity. Timecourses of image intensity for each spatial location in the brain may be extracted for examination in further steps.

[0047] 4. Transform of the Timecourse: The transform (e.g., fourier transform or wavelet transform) of the timecourse is computed to create a spectrum. The spectrum provides information about the magnitude of brain activity at various specific frequencies and within various defined frequency bands such as delta (~l-4Hz).

[0048] 5. Deconvolution of the hemodynamic response function (HRF): Using Fourier convolution theorem, the electrophysiological activity timecourse is recovered by mathematically deconvolving the temporal blur introduced by the hemodynamic response function (hrf) from the observed signal.

[0049] 6. Construction of Spectrogram of Brain Activity: A sliding window along the timecourse is used to compute a series of spectrums corresponding to various timepoints of the MR exam. The spectrogram is used to measure and visualize changes to the brain’s electrophysiological spectrum over time and at a specific defined point in the brain.

[0050] 7. Construction of a Spatial Map of Spectral Activity: An image which has intensity modulated by the power contained in a defined frequency band (as suggested by the spectra of step 4 or 5) - such as the delta wave band - may be constructed to examine and measure the spatial distribution of brain activity.

[0051] 8. Detection of alterations to Brain Activity in Disease, Injury, or Sleep: Alterations to brain activity may be visualized or statistically tested with the FFT of the timecourse, the spectrogram, or the spatial map of spectral activity. A patient’s spectral measures may be compared to a healthy control benchmark measure. In brain conditions such as concussion or dementia, this method is sensitive to alterations to brain activity. As stated hereinabove, the alteration in brain activity may be in comparison to a reference from a healthy control; comparison to a reference from a subject with a brain pathology; and / or in comparison to the subject prior to an event (e.g., a brain injury). The alteration in brain activity may be an increase or decrease in brain activity in a particular location or area of the brain and / or at a particular time. In certain embodiments, when the brain activity of the subject corresponds to or matches the brain activity from a healthy control, it indicates that the subject does not have a brain pathology. In certain embodiments, when the brain activity of the subject corresponds to or matches the brain activity from a subject with a brain pathology, it indicates that the subject has the particular brain pathology. In certain embodiments, the methods of the instant invention may comprise actively performing the analysis on the positive and / or negative control samples or may comprise comparison to previously performed experiments (e.g., standards). In certain embodiments, when the brain activity of the subject is altered to the brain activity from the subject prior to an event (e.g., a brain injury), it indicates that the subject has a brain pathology.

[0052] The methods of instant invention may further comprise treating a brain pathology (e.g., by administering a therapy (e.g., non-pharmaceutical) and / or therapeutic agent (e.g., a compound or pharmacological agent or drug)) in the subject (e.g., diagnosed as having a brain pathology). In certain embodiments, the method comprises administering a therapeutically effective amount of a therapeutic agent. In certain embodiments, the methods further comprise treating a subjected determined to have had a traumatic brain injury or concussion with a traumatic brain injury therapeutic (e.g., a solution (e.g., oral) comprising branched chain amino acids (e.g., valine, leucine, and / or isoleucine (e.g., U.S. Patent Application Publication No. 20160058726, incorporated herein by reference))). In certain embodiments, the methods further comprise treating a subjected determined to have Alzheimer’s disease with an Alzheimer’s disease therapeutic (e.g., donanemab (Kisunla™), lecanemab (Leqembi®), cholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine), and memantine). In certain embodiments, the methods further comprise treating a subjected determined to have dementia with a dementia therapeutic (e.g., cholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine) and memantine). In certain embodiments, the methods further comprise treating a subjected determined to have epilepsy with an epilepsy therapeutic (e.g., anti-epileptic drugs (AEDs) (e.g., sodium valproate, carbamazepine, lamotrigine, levetiracetam, topiramate, brivaracetam, clobazam, clonazepam, diazepam, ethosuximide, gabapentin, lacosamide, midazolam, oxcarbazepine, perampanel, phenobarbitone, phenytoin, pregabalin, primidone, rufinamide, tiagabine, vigabatrin, and zonisamide), brain surgery, vagus nerve stimulation, deep brain stimulation). In certain embodiments, the methods further comprise treating a subjected determined to have Parkinson’s disease with a Parkinson’s disease therapeutic (e.g., levodopa (L- dopa), carbidopa, sinemet, pramipexole, rotigotine, ropinirole, enacarbil, gabapentin, amantadine, anticholinergics (e.g., benzotropine and trihexyphenidyl), Mao-B inhibtiors (e.g., safinamide, selegiline, and rasagiline), and COMT inhibitors (e.g., entacapone, opicapone, and tolcapone). In certain embodiments, the methods further comprise treating a subjected determined to have had a stroke with a stroke therapeutic (e.g., cholesterol lowering drug (e.g., statin), thrombolytic drug (e.g., tissue plasminogen activator), antiplatelet drug (e.g., acetylsalicylic acid (ASA), clopidogrel, and ticlopidine), and anticoagulant (e.g., heparin and warfarin)). In certain embodiments, the methods further comprise treating a subjected determined to have a tumor (e.g., brain tumor) with a tumor (e.g., brain tumor) therapeutic (e.g., a chemotherapeutic agent (e.g., temozolomide, carmustine (BCNU), irinotecan, lomustine (CCNU), procarbazine, vincristine, carboplatin, cisplatin, etoposide, and bevacizumab), brain surgery (e.g., excise tumor), and radiation therapy). In certain embodiments, the methods further comprise treating a subjected determined to have a cerebral edema with a cerebral edema therapeutic (e.g., corticosteroids (e.g., dexamethasone) and brain surgery). In certain embodiments, the methods further comprise treating a subjected determined to have a sleep disorder with a sleep disorder therapeutic (e.g., melatonin, zolpidem, zaleplon, eszopiclone, benzodiazepine, orexin receptor antagonist (e.g., daridorexant, lemborexant, and quetiapine), and antinarcoleptics (e.g., pitolisant and sodium oxybate).

[0053] In certain embodiments, the methods of the instant invention are performed within about 3 weeks after a purported event (e.g., a purported traumatic brain injury). In certain embodiments, the method is performed within about 3 weeks, 2, weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less after the event. In certain embodiments, the method is performed within about 48 hours after the event. In certain embodiments, the method is performed within about 36 hours, about 24 hours, about 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, or about 1 hour after the event.

[0054] The methods of the instant invention can be performed at more than one timepoint after the event (e.g., purported traumatic brain injury or concussion). In certain embodiments, the method is performed multiple times so as to generate a timecourse. By taking multiple assessments, the recovery from the brain pathology (e.g., traumatic brain injury) and / or efficacy of a treatment can also be monitored (e.g., by determining if brain activity returns to normal). In accordance with the instant invention, methods of determining the efficacy of a treatment against a brain pathology (e.g., traumatic brain injury) are provided, wherein the method comprises determining if the brain activity of a subject having a brain pathology (e.g., traumatic brain injury) and administered the therapy returns to normal faster than a subject having a brain pathology (e.g., traumatic brain injury) without therapy. In certain embodiments, the method comprises administering a therapy to a subject and detecting and / or measuring the brain activity of the subject at a later time point, optionally more than once. The method may further comprise detecting and / or measuring the brain activity of the subject before and / or at the time of the administration of the therapy (e.g., as a baseline).

[0055] The therapeutic agent may be administered as part of a composition with a pharmaceutically acceptable carrier. The compositions of the instant invention may be conveniently formulated for administration with any carrier, particularly any pharmaceutically acceptable carrier(s). Except insofar as any conventional carrier is incompatible with the agents to be administered, its use in the pharmaceutical composition is contemplated. For example, the active agents may be formulated with an acceptable medium such as sterile liquid, water, aqueous solutions, buffered saline, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), dimethyl sulfoxide (DMSO), oils, detergents, suspending agents or suitable mixtures thereof. The concentration of the active agents in the chosen medium may be varied and the medium may be chosen based on the desired route of administration of the pharmaceutical preparation. Except insofar as any conventional media or agent is incompatible with the active agents to be administered, its use in the pharmaceutical preparation is contemplated.

[0056] The compositions of the present invention can be administered by any suitable route, for example, by infusion, injection or other modes of administration such as controlled release devices. In certain embodiments, the composition is delivered by injection. In certain embodiments, the composition is delivered directly to the brain. In general, pharmaceutical compositions and carriers of the present invention comprise, among other things, pharmaceutically acceptable buffers, diluents, liquids (such as water, saline, glycerol, sugars and ethanol), preservatives, stabilizing agents, solubilizers, emulsifiers, wetting agents, pH buffering substances adjuvants and / or carriers. Such compositions can include diluents of various buffer content (e.g., saline, Tris HC1, acetate, phosphate), pH and ionic strength; and additives such as detergents and solubilizing agents (e.g., polysorbate 80), anti oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., benzyl alcohol) and bulking substances (e.g., lactose, mannitol). For example, the preparation can be formulated with a buffer containing salts, such as NaCl, CaCh, and amino acids, such as glycine and / or lysine, and in a pH range from 6 to 8. The pharmaceutical compositions may be formulated in aqueous solutions (e.g., physiologically compatible buffers). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. The compositions of the invention may also be incorporated into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes or micelles, or mixed with phospholipids or micelles to increase stability. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of components of a pharmaceutical composition of the present invention. Exemplary pharmaceutical compositions and carriers are provided, e.g., in “Remington’s Pharmaceutical Sciences” by E.W. Martin (Mack Pub. Co., Easton, Pa.) and “Remington: The Science and Practice of Pharmacy” by Alfonso R. Gennaro (Lippincott Williams & Wilkins) which are herein incorporated by reference. The pharmaceutical composition of the present invention can be prepared, for example, in liquid form, deep-frozen, or can be in dried powder form (e.g., lyophilized). In a particular embodiment, when the preparation is stored in lyophilized form, it may be dissolved into a visually clear solution using an appropriate reconstitution solution prior to administration.

[0057] The compositions described herein will generally be administered to a patient as a pharmaceutical preparation. The term “patient” or “subject”, as used herein, refers to human or animal subjects. The compositions of the instant invention may be employed therapeutically, under the guidance of a physician.

[0058] The dose and dosage regimen of the compositions according to the invention that are suitable for administration to a particular patient may be determined by a physician considering the patient’s age, sex, weight, general medical condition, and the specific condition for which the active agent is being administered and the severity thereof (e.g., the severity of the bleeding). The physician may also take into account the route of administration, the pharmaceutical carrier, and the particular agent’s biological activity.

[0059] Selection of a suitable pharmaceutical preparation will also depend upon the mode of administration chosen. For example, the compositions of the invention may be administered by direct injection to a desired site. In this instance, a pharmaceutical preparation comprises the active agents of the instant invention dispersed in a medium that is compatible with the site of injection. The compositions of the instant invention may be administered by any method. For example, the compositions can be administered, without limitation, intravenously. Pharmaceutical preparations for injection are known in the art. If injection is selected as a method for administering the compositions, steps must be taken to ensure that sufficient amounts of the molecules reach their target cells to exert a biological effect.

[0060] A pharmaceutical preparation of the invention may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to a physically discrete unit of the pharmaceutical preparation appropriate for the patient undergoing treatment. Each dosage should contain a quantity of active ingredient calculated to produce the desired effect in association with the selected pharmaceutical carrier. Procedures for determining the appropriate dosage unit are well known to those skilled in the art. Dosage units may be proportionately increased or decreased based on the weight of the patient. Appropriate concentrations for alleviation of a particular pathological condition may be determined by dosage concentration curve calculations, as known in the art. Definitions

[0061] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0062] As used herein, the term “subject” refers to an animal, particularly a mammal, particularly a human.

[0063] The term “pathology” refers to any deviation from a healthy or normal condition, such as a disease, disorder, syndrome, or any abnormal medical condition.

[0064] As used herein, “diagnose” refers to detecting and identifying a disease in a subject. The term may also encompass assessing, evaluating, and / or prognosing the disease status (progression, regression, stabilization, response to treatment, etc.) in a patient known to have the disease.

[0065] As used herein, the term “prognosis” refers to providing information regarding the impact of the presence of a disease or disorder (e.g., TBI) on a subject’s future health (e.g., expected morbidity or mortality, the likelihood of developing a disease or disorder (e.g., cognitive impairment), and the severity of the disease or disorder). In other words, the term “prognosis” refers to providing a prediction of the probable course and outcome of the disease or the likelihood of recovery from the disease or disorder.

[0066] “Pharmaceutically acceptable” indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0067] A “carrier” refers to, for example, a diluent, adjuvant, preservative (e.g., Thimersol, benzyl alcohol), anti-oxidant (e.g., ascorbic acid, sodium metabisulfite), solubilizer (e.g., polysorbate 80), emulsifier, buffer (e.g., Tris HC1, acetate, phosphate), antimicrobial, bulking substance (e.g., lactose, mannitol), excipient, auxiliary agent or vehicle with which an active agent of the present invention is administered. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E.W. Martin (Mack Publishing Co., Easton, PA); Gennaro, A. R., Remington: The Science and Practice of Pharmacy, (Lippincott, Williams and Wilkins); Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y.; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington.

[0068] The following examples are provided to illustrate various embodiments of the present invention. They are not intended to limit the invention in any way.

[0069] EXAMPLE 1

[0070] MRI Acquisition

[0071] Ultra-fast magnetic resonance encephalography (MREG) exhibits blood oxygen level dependent (BOLD) imaging contrast which is sensitive to the brain’s hemodynamic response to activated neurons. MREG is acquired with a repetition time (-O.lsec) faster than conventional echo-planar fMRI (~2-3s) and can achieve a sampling rate on the order of 10Hz. Shorter MREG repetition rates can offer sensitivity to brain activity at yet higher frequencies (such as theta, alpha, beta or gamma), thereby opening up yet further applications of “spectrally-selective fMRI” or studies of spatiospectrotemporal dynamics of brain neuronal activity.

[0072] MREG may be acquired in a subject in the resting state, sleeping state, or taskexecuting state, depending on the specific application. For patients with brain injury including traumatic brain injury or concussion, Alzheimer’s, dementia, epilepsy, or Parkinson’s, the subject may be at rest because abnormal endogenous alterations to brain activity will be continual or without regard to consciousness or task.

[0073] During sleep, the Delta wave (~0. l-4Hz) activity in the brain is known to increase. The demonstration subject fell asleep ~15 minutes into the approximately 1- hour scan and was allowed to sleep for approximately 30 minutes. At a known point in time, the subject was woken up. For the example data shown, a healthy adult subject was continuously scanned with an MREG (Siemens C2P) sequence on a 3T Prisma with a 32-channel head coil, TR of 100ms, 64x64x64 matrix, and 3mm isotropic resolution for approximately 1 hour, during wakefulness and sleep as described above. The MREG image reconstruction creates a 4D image matrix with dimensions V=[x,y,z,t] where x,y,z are the spatial dimensions and t is the time dimension. The image matrix is truncated to remove timepoints prior to steady-state stabilization of the MR signal. From the 4D image matrix, any individual point in space r=[rx,ry,rz] may be enumerated to create a timecourse signal s(r,t)=V[rx,ry,rz,t]. A post-processing motion correction may be applied, but was not for the example data shown.

[0074] Post Processing

[0075] Simulations of the post processing procedure were performed in python to illustrate the procedure and demonstrate the theory of measuring brainwave and brain spectral activity from the MREG timecourse (Figures 1A and IB). Brain activity at 0.25Hz was simulated using a half-rectified sine wave. The activity was convolved with a hemodynamic response function modeled with the Gamma Variate curve to produce a signal simulating the BOLD contrast sampled by the MREG signal (Fig. 1 A). Other function forms, or direct assays, of the hemodynamic response function might also be employed. The simulated measured MREG signal has a clear peak in oscillatory activity at 0.25Hz and demonstrates that the measured MREG signal retains the oscillatory characteristics of the original electrophysiological brain activity, even after being convolved with a slow hemodynamic response. As shown, it is possible to plot the spectral activity of brain activity of each position in the brain. Furthermore, the spectral activity may be examined for various time window widths centered on arbitrary timepoints of the collected MREG exam. The original brain wave activity may be estimated through the multiplicative property of the Fourier transform by dividing the spectrum by the spectrum of the hemodynamic response curve (Fig. IB).

[0076] The postprocessing pipeline to detect brain spectral activity was applied to the real MREG data from the wake / sleep / wake participant (Figures 2A-2C). An MREG timecourse from the frontal cortex was selected. The MREG timecourse was highpass filtered to demean the timecourse but retain activity over 0.005Hz. The timecourse is depicted in Figure 2A and spans approximately 45 minutes with 25000 points and a sampling rate of 100ms. The time period during which the subject was sleeping is estimated with the arrow. The exact timepoint the subject fell asleep is not precisely known. However, the subject was woken up at the identified timepoint. During the sleep period, increased brain activity can be visualized directly from the MREG timecourse. A spectrogram across the study time is computed to visualize brain activity spectral pattern dynamics for one brain location (Fig. 2B). A bandpass filter across the spectrogram or timecourse is used to compute a plot of spectral band power as a function of time (Fig. 2C). In this example, the spectrogram power signature changes during sleep, demonstrating sensitivity to altered brain activity during sleep. Analogously, the frequency-selected slow wave (2.5-4Hz) power graph shows an elevation in spectral band power during sleep. The magnitude of brain activity power, the temporal derivative of brain activity power, and statistical comparisons between timepoints or control benchmarks may be similarly computed and visualized as a function of time or space.

[0077] EXAMPLE 2

[0078] Herein, magnetic resonance encephalography (MREG) is applied for detection and observation of endogenous slow brain activity (delta band, <4 Hz). MREG (Hennig, et al. (2021) Magma, 34(1): 85- 108) is a parallel-accelerated, stack of spirals trajectory pulse sequence which provides faster image acquisition than conventional fMRI and superior spatial localization than EEG / MEG and thus can be considered “delta wave MRI”. The sensitivity of MREG to delta wave activity is illustrated by comparing signal spectra between sleep and awake states, although any occurrence of delta wave activity could be similarly imaged.

[0079] BOLD MR contrast is dependent on temporal changes in the relative concentrations of oxyhemoglobin and deoxyhemoglobin and relies on the sensitivity of T2*- weighted EPI to local magnetic field homogeneity (Ogawa, et al. (1990) Proc. Natl. Acad. Sci., 87(24):9868-9872). However, the event-driven dynamics of oxy- and deoxy-hemoglobin levels only provide a secondary, surrogate marker for brain activity and are not necessarily temporally aligned with neuronal activity. Blood exchange at the cortex is controlled by the hemodynamic response mechanism which lags neuronal activity and introduces a temporal convolution or smearing to the BOLD signal relative to the underlying brain activity. In traditional “box-car” and event-related fMRI, the dominant hemodynamic response to a relatively large and sustained brain activity takes approximately 5 seconds to peak (DEsposito, et al. (1999) Neuroimage, 10(1 ):6- 14). However, recent studies have shown that the hemodynamic response to steady state brain activity and smaller endogenous oscillations is more localized and rapid than the large and slow hemodynamic response modeled and observed in event-triggered fMRI studies (Polimeni, et al. (2021) Prog. Neurobiol,, 207: 102174). The existence of a rapid BOLD response which fluctuates on the same time scale as natural or ongoing brain activity critically enables faster fMRI to detect slow neural activity (Lewis, et al. (2016) Proc. Natl. Acad. Sci., 113(43):E6679-E6685).

[0080] Delta wave MRI provides ultra-fast whole brain BOLD imaging which, in turn, translates to detection of higher frequency brain oscillations. Conventional echo-planar fMRI acquires whole brain volumes at a rate of approximately 2-3 seconds per volume (with approximate sampling frequency of 0.33-0.5 Hz and Nyquist bandwidth of 0.17-0.25 Hz). Delta wave MRI uses a single shot “stack of spirals” trajectory, as well as image acquisition acceleration, to acquire whole brain volumes at a much faster rate of ~0.1 s per volume (Hennig, et al. (2021) Magma, 34(1): 85-108; Hennig, et al. (2007) Neuroimage, 34(1):212-219; Lee, et al. (2013) Proc. Inti. Soc. Mag. Reson. Med., 21 :3277). This sampling rate of 10 Hz enables detection of fluctuating signals (brain oscillations) up to 5 Hz in accordance with the Nyquist limit. As discussed above, assuming the hemodynamic response to natural and slow brain oscillations is rapid, the hemodynamic response will not be substantially smoothed or convolved relative to the underlying brain activity. Unlike in conventional fMRI which suffers from a large, slow hemodynamic response, the delta wave MRI BOLD signal is thus directly examined without the need to remove or deconvolve the hemodynamic response function.

[0081] Herein, methods are presented herein for using ultra-fast MR encephalography to measure and visualize a spectrogram of electrophysiological brain activity in the ~l-4 Hz band: delta wave MRI. Although this activity is referred to as “slow” on an electrophysiological scale, this is much faster than typical BOLD fMRI sensitivity. Subject sleep state is used to illustrate the sensitivity of the technique to changes in brain activity since delta band activity is well known to increase during sleep (Dang- Vu, et al. (20080) Proc. Natl. Acad. Sci., 105(39): 15160-15165; Song, et al. (2022) Proc. Natl. Acad. Sci., 119(30):e2016732119). The framework of using ultra-fast delta wave MRI to detect alterations to low frequency band brain activity has applications to multiple conditions and diseases which cause pathologic slow (delta) wave activity including traumatic brain injury, stroke, brain tumor, epilepsy, Alzheimer’s disease and Parkinson’s disease.

[0082] Methods An overview of the method framework is shown in Figure 3. Briefly, ultrafast MREG is acquired at 0.1 s temporal resolution and reconstructed. The MREG reconstruction is a 4D volume comprising three spatial dimensions and a temporal dimension, analogous to conventional fMRI 4D volumes. Spatial resolution is comparable to typical fMRI paradigms (~3mm). At each spatial location (voxel), the brain activity waveform and / or power spectrum may be extracted and computed. Frequency and spatial information may be combined to create an image of spectral power across the brain.

[0083] MRI Acquisition

[0084] The MR acquisition was performed on a 3T Prisma (version VE11C) with a 32 channel RF head coil, TR of 100 ms, TE 20ms, 15° flip angle, 4x64x64 matrix, field of view 192x192x192 mm, and 3 mm isotropic resolution. The stack of spirals MREG pulse sequence was C2P Package Version 2.3 (Asslander, et al. (2013) Neuroimage, 73:59-70).

[0085] A healthy adult subject (male, age 56 years) was continuously scanned with the MREG sequence for 45 minutes, during wakefulness and sleep. To ease the computational demands of reconstruction, the MREG sequence was limited to 3.5 minutes and repeated 13 times consecutively during the subject’s MR exam, over the course of approximately 45 minutes. The scanner was set to automatically proceed to the next MREG sequence to limit non-scan time-gap between sequences. The subject was instructed to lay motionless in the scanner and to allow themselves to fall asleep. Following the MREG acquisition the subject reported being aware of approximately 3-4 sequence “gaps” (~15 minutes) before falling asleep. Approximately 35 minutes after onset the subject was awoken and scanning continued for another 10 minutes. Thus, an extended “box-car” of awake / drowsy - sleep - awake was achieved with -15:20:10 minute blocks.

[0086] Reconstruction

[0087] Non-Cartesian data from each of the 13 MREG scans was reconstructed independently using an iterative regularization MATLAB reconstruction algorithm provided with the MREG sequence, yielding a 4D image matrix with dimensions V=[x,y,z,t] where x,y,z are the spatial dimensions and t is the time dimension. The image matrix for each MREG segment was truncated to remove the first 60 timepoints corresponding to 6s (~2-3 Tls) prior to steady-state stabilization of the MR signal. Reconstructed MREG image matrices were then concatenated along the time domain yielding a single 4D image matrix for the entire (45 minute) scan. The dataset was motion-corrected with 6 degrees of freedom using FSL FLIRT. From the 4D image matrix, any individual position in space r=[rx,ry,rz] may be enumerated to create a timecourse signal s(r,t)=V[rx,ry,rz,t]. An MREG timecourse s(r,t) may thus be selected from any voxel in the brain. The MREG timecourses were then highpass filtered with a Butterworth filter and cutoff frequency of 0.01Hz to remove ultra-low frequency activity and DC-offset. Spectrograms from 50 s frames were then computed for each voxel’s MREG timecourse using the spectrogram function from python’s SciPy package (scipy.org / citing-scipy / ), which computes consecutive Fourier transforms.

[0088] Results

[0089] Figure 4 demonstrates that the spatial distribution of delta power may be visualized across the brain. Full delta band power between 0.2Hz and 4Hz was averaged over a 50 s period for every voxel in the brain during the initial awake period, the sleep period, and the final awake period. Power is expressed in arbitrary units related to BOLD signal intensity. Peak delta power was localized primarily in brain periphery and sulcal regions, consistent with cortical tissue. During the sleep state, delta power was observed to be elevated in cortical regions throughout the cerebrum.

[0090] Figure 5A shows the whole brain voxel-wise t-statistic map of slow wave (0.2- 4 Hz) power difference between sleep and awake. Delta band power was contrasted with a student t-test for an asymmetric boxcar of 250 s awake, 500 s sleep, and 250 s sleep. The time and frequency domain MREG waveforms of a single temporal cortex voxel are shown in Figures 5B-5D. The arrows along the time axis represent the approximate time period the subject was asleep. While the exact time the subject transitioned into sleep is unknown, the subject stopped reporting being awake about 10 to 15 minutes into the scan and was, thus, presumed asleep. The subject was abruptly woken up at the time indicated by the vertical arrow.

[0091] An example temporal cortex voxel’s time domain MREG waveform (sampling frequency 10 Hz) is shown across the entire experiment in Figure 5B. A distinct change in waveform amplitude and signal appearance is appreciated during the period of sleep. The associated spectrograms of slow wave power over time (0.25 to 5 Hz and Figure 5C and 5D) shows an increase in power during the sleep period as compared to the awake periods at the beginning and end of the recording. The spectrogram visualizes changing power in specific frequency bands during the recording, also referred to as the “spectrotemporal neural dynamics.” Elevated power during sleep is observed at 0.25 Hz in addition to elevated power in frequencies above 1 Hz.

[0092] Herein, the utility of combining ultrafast MREG BOLD acquisition with spectrally selective filtering to detect and localize selected electrophysiological brain activity using MRI has been demonstrated. Specifically, the feasibility of selecting and imaging power in the delta frequency band (-0.1-4 Hz) has been demonstrated. Spatial foci and temporal dynamics can be probed, revealing the timecourse and spectral patterns of wakefulness and sleep.

[0093] This application of ultra-fast MREG in combination with a rapid hemodynamic response allows for MR imaging delta waves. The 10 Hz BOLD sampling afforded by the MREG pulse sequence mathematically allows for measuring oscillations up to 5 Hz, capturing the electrophysiologically-termed “delta” band. High frequency oscillatory activity above the delta band is not captured and, thus, measured delta activity could not be normalized to broadband activity.

[0094] In contrast to large-elicited brain responses, endogenous delta activity involves assemblies of neurons firing in synchrony at delta frequencies. The approximately 0.25 Hz peak has been shown in EEG and conventional fMRI to be associated with sleep spindles, as well as the more well-known “slow waves” (l-4Hz) characteristic of “slow-wave sleep” (Song, et al. (2022) Proc. Natl. Acad. Sci., 19(30):e2016732119; Vayrynen, et al. (2023) Clin. Neurophysiol., 156:207-219). This more naturalistic and ongoing brain activity does not elicit a large hemodynamic response, but rather a short-lived increase in deoxyhemoglobin akin to the negative BOLD dip described in conventional fMRI (Bandettini, et al. (1992) Magn. Res. Med., 25(2):390-397). Either the local perfusion changes are small or possibly the perfusion remains constant and provides a continual supply of oxyhemoglobin which rapidly displaces deoxyhemoglobin. The interpretation of the MREG signal dynamics is enabled by the key assumption of a hemodynamic response matched to the time scale of the delta activity which is based on a body of literature describing fMRI’s ability to detect activity faster than would be possible if the hemodynamic response were as slow as 5 seconds (Polimeni et al. (2021) Prog. Neurobiol., 207: 102174; Lewis, et al. (2016) Proc. Natl. Acad. Sci., 113(43):E6679-E6685; Chen, et al. (2011) Neuroimage, 54(2): 1021-30).

[0095] Alterations to delta waves (~l-4 Hz) are known to be hallmarks of anomalous brain activity in a variety of neurologic and pathologic conditions. The presently- demonstrated delta wave MRI method can identify and monitor the spatial localization of pathologic neural spectro-temporal features. Clinical opportunities are based on the following known observations: elevated resting state delta-band activity is a common observation across conditions where neuronal deafferentation or degenerative damage has occurred with trauma, stroke, edema, Alzheimer’s disease or tumor infiltration (Brenner, et al. (1986) Electroencephalogr. Clin. Neurophysiol., 64(6):483-492; Jeong, J. (2004) Clin. Neurophysiol., 115(7): 1490-1505). Specifically, MEG methods have also been demonstrated to be sensitive to enhanced and localizable slow wave activity in traumatic brain injury (Huang, et al. (2014) NeuroImage: Clin., 5:109-119). However, the spatial resolution of MEG is limited and reliant upon a separate MRI exam to perform subject-specific source localization. A technique such as delta wave MRI provides inherent spatial localization along with the required spectral sensitivity and reduces the need for additional imaging test for patients already undergoing MRI.

[0096] In summary, the demonstrated MR technique for measuring brain slow wave activity is sensitive to changes in the magnitude and frequency of brain activity in sleep. These methods can be extended to study a variety of pathologies. The technique of delta wave MRI (or more broadly “frequency selective brainwave MRI”) will prove efficacious in diagnosis, prognosis and monitoring therapeutic interventions in a range of neurologic conditions, characterized by delta-band (slow- wave) oscillopathy.

[0097] While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims.

Claims

What is claimed is:

1. A method for detecting or diagnosing a brain pathology in a subject, said method comprising performing an ultrafast blood oxygen level dependent (BOLD)-sensitive magnetic resonance imaging (MRI) on the subject, wherein the ultrafast MRI is at least 10 frames per second, and detecting an alteration in brain activity, wherein the brain activity is limited to brain waves less than approximately 4 Hz, and wherein the alteration of brain activity in the subject is indicative of said brain pathology.

2. The method of claim 1, wherein said ultrafast BOLD-sensitive MRI is an ultrafast magnetic resonance (MR) encephalography (MREG).

3. The method of claim 1, wherein said detecting an alteration in brain activity comprises comparing the brain activity in said subject with a reference from a healthy control; comparing the brain activity in said subject with a reference from a subject with a brain pathology; and / or comparing the brain activity in said subject with the brain activity of the subject prior to a purported brain pathology inducing event.

4. The method of claim 1, further comprising diagnosing the subject with a brain pathology based on the detected alteration in brain activity.

5. The method of claim 1, further comprising administering a therapy and / or therapeutic agent to said subject for the treatment of said brain pathology.

6. The method of claim 1, wherein the brain activity is limited to brain waves of about 0.1 Hz to 4.0 Hz.

7. The method of claim 1, wherein said brain pathology is a traumatic brain injury or a concussion.

8. The method of claim 1, wherein said brain pathology is Alzheimer’s disease.

9. The method of claim 1, wherein said brain pathology is epilepsy.

10. The method of claim 1, wherein said brain pathology is Parkinson’s disease.

11. The method of claim 1, wherein said brain pathology is a brain tumor.

12. The method of claim 1, wherein said brain pathology is a stroke.

13. The method of claim 1, wherein said brain pathology is cerebral edema.

14. The method of claim 1, wherein said brain pathology is a sleep disorder.

15. A method for monitoring a therapy against a brain pathology, said method comprising: a) administering a therapy to a subject with said brain pathology; and b) performing an ultrafast blood oxygen level dependent (BOLD)-sensitive magnetic resonance imaging (MRI) on the subject, wherein the ultrafast MRI is at least 10 frames per second, and c) detecting an alteration in brain activity, wherein the brain activity is limited to brain waves less than approximately 4 Hz, wherein a decrease in the alteration in brain activity indicates that the therapy is effective against said brain pathology.

16. The method of claim 15, wherein said ultrafast BOLD-sensitive MRI is an ultrafast magnetic resonance (MR) encephalography (MREG).

17. The method of claim 15, wherein steps b) and c) are performed more than once.

18. The method of claim 15, further comprising determining the baseline of the subject by measuring the brain activity in said subject prior to the administration of the therapy.

19. A method for measuring brain activity in a subject, said method comprising performing an ultrafast blood oxygen level dependent (BOLD)-sensitive magnetic resonance imaging (MRI) on the subject, wherein the ultrafast MRI is at least 10 frames per second, and detecting said brain activity, wherein the brain activity is limited to brain waves less than approximately 4 Hz.

20. The method of claim 19, wherein said ultrafast BOLD-sensitive MRI is an ultrafast magnetic resonance (MR) encephalography (MREG).

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