Patent Application
20170172495
The present invention relates to a method and system for using neurochemical markers to identify different types of pain, including chronic and acute, and providing the capacity to monitor response to therapy on an individual basis. The present invention relates to a method and system for using neuro biomarkers to identify pain of different types and origins, and the capacity to monitor response to therapy on a personalized basis.
This patent application cites various publications and other documents. These publications and documents are hereby incorporated by reference.
Evidence based medicine is currently used to manage chronic pain i.e. each individual's clinical management is based on the outcomes from other people. The flaw in this approach is that risk of acute and chronic pain and response to treatment varies from person to person due to differences in genetic makeup, environmental exposure and insult to the body and type of pain. Personalized medicine is now being implemented from research outcomes where innovations are designed to customize care [1]. However its success is critically dependent on the reliability and increased precision for diagnosis and monitoring therapy. There are different origins and types of chronic pain. Distinguishing between these categories by an objective means is important for the patient and the healthcare budget.
Pain is one of the most expensive health problems [2], costing the Australian economy, for example, around $34 billion every year [3]. Chronic pain significantly impairs quality of life, as manifested by poorer mental and physical function, work productivity, relationships and sleep.
The present invention provides a system and method for using 2D COSY to detect pain. The present invention is also directed to using two dimensional (2D) neuro magnetic resonance spectroscopy (MRS) to detect neurochemical markers to identify and distinguish between from different origins. Neurochemical markers that alter with chronic pain, including neuropathic pain, nociceptive pain, chronic prostatitis/pelvic pain syndrome (CP/CPPS) and irritable bowel syndrome (IBS) can be identified by 2D MRS, and more particularly 2D COSY. An objective diagnosis can be made for each of these pain types where in some cases further subcategorization is possible. The biomarkers can improve clinical management by providing a definitive diagnosis; an understanding of the biological pathways; and for the first time a means to objectively test new therapies.
MR technology, two-dimensional (2D) MR spectroscopy, allows definitive assignment of neurochemicals that alter with pain, head injury and a range of neurological diseases.
The invention provides a system and method to apply MR technologies to document the neurochemical effects of chronic pain of different types and origins.
The MR data can be analyzed by a modern informatics and now shown to be effective for a study on chronic pelvic pain syndrome, neuropathic and noiciceptive pain. The outcome can yield informatics outcomes for automated specific molecular information on altered pathways for the development of improved pharmacologic intervention; the capacity to monitor therapy; and tools for clinical assessment of recovery.
How chronic pain alters brain chemistry can be monitored by neuromagnetic resonance spectroscopy (MRS). In contrast to morphological magnetic resonance imaging (MM), or functional MRI (fMRI) which characterizes temporal differences in brain activity in response to stimulation, MRS monitors changes in the chemical activity in the brain. It is suggested [4] that neuro MRS identifies the earliest changes to the brain. Neuro MRS can be correlated with modern techniques such as diffusion tensor imaging (DTI) and susceptibility weighted imaging (SWI).
Clinically there is significant overlap between chronic pain from conditions such as irritable bowel and other poorly understood chronic pain condition syndromes including CP/CPPS [5]. These are clinically distinguishable from the more established neuropathic and noiciceptive types of chronic pain. One can use one-dimensional (1D) MRS, two-dimensional (2D) COrrelated SpectroscopY (COSY) and separate neuropathic from Noiciceptive from CP/CPPS cohort from the controls (p<0.01). The diagnostic spectral regions identified by 2D MRS can be assigned to free and bound fucose, and glutamate and glutamate as well as other markers such as choline. The terminal fucoslyated molecules are understood to be associated with the inflammatory process as well as normal brain activities. The level of pain can be determined by analysis of the MRS data. In contrast to neurochemical changes from neuropathic and noiceptive pain [6-8] which includes glutamatergic dysfunction, CP/CPPS does not exhibit glutamatergic dysfunction and can be subcategorized.
A preferred embodiment will be described as one way of practicing the invention, but the invention is not limited to this embodiment.
Using 2D MRS data, one can assign the diagnostic molecules and identify the neurochemical pathways that alter with each type of pain, such as chronic pain and its various types.
The chemicals that alter the neurochemical pathways reflect specific pathways that have been altered as a function of the origin of the chronic pain.
One can detect several different subcategories of chronic pain: those with glutamatergic dysfunction and those without. For example neuropathic and nociceptive pain will include glutamatergic dysfunction as well as fucosylated markers. IBS and CP/CPPS will not have glutamatergic dysfunction but will have fucosylated markers. There will be at least two different types of fucoslyated markers distinguishing neuropathic from other types of pain.
Central sensitization, contributes to inflammatory, neuropathic, and functional pain [10]. This hypersensitivity arises when the pain pathways increase in sensitivity when relaying pain messages. It is suggested that fibromyalgia and IBS could be manifestations of altered function of the nervous system involving central sensitization [10]. Deregulation of the acute tryptophan depletion brain network is thought to promote central pain amplification in IBS [11] which is difficult to correct A biomarker(s) of central sensitization [12] would be important. Biomarkers for inflammation have been identified and their role in the amplification process can thus be considered.
Early in vivo spectroscopy studies undertaken in neuropathic pain patients reported a reduction in NAA and glucose in the prefrontal cortex (PFC) in chronic low back pain sufferers [13] and reduction of NAA in the thalamus [14]. More recent studies, with improved MRS technology, on chronic low back pain and migraine cohorts [6-8] have shown glutamatergic dysfunction known to cause neuronal damage above certain levels [15]. A personalized medicine approach will in the future provide an understanding of pain biology.
Described as a “virtual biopsy”, MRS obtains chemical information from specific regions of interest (ROI or voxel). Neuro metabolites relevant to chronic pain, diseases, degeneration and psychological categories can be measured relative to each other [8]:
With sufficient numbers in each category the 1D MRS method can be analyzed by robust mathematical methods removing the need for a reader.
In the 1D spectrum many resonances are composites and/or overlap. Two dimensional (2D) MRS, COrrelated SpectroscopY (COSY), can be employed in vivo to separate resonances in a second magnetic frequency (
Our recent studies have shown that the neurochemical changes from neuropathic and noiceptive pain i.e. chronic low back pain [7], chronic pain from spinal cord injury [8] and migraine [6] have some commonalty and some differences.
The 2D COSY method confirmed glutamatergic dysfunction i.e. increased levels of glutamate/glutamine in chronic noiceptive (osteoarthritis) and neuropathic (postherpetic neuralgia) pain but have yet to confirm if glutamine and or glutamate, or both, that are increasing. Glutamate, an excitatory neurotransmitter, is predictive of poor outcome when elevated in severe traumatic brain injury [23]. The concept of the excitory amino acids, particularly glutamate, having a role in neurologic disorders has been discussed [24]. Other differences include increases in choline and myoinositol.
The assignment of fucosylated molecules in the brain was made possible by the 2D method and modern MR scanner technology [9]. Four fucosylated species have been assigned [25] in cancer cell models and in vivo in glioma [9]. Finding similar species in 2D spectra from neuropathic pain patient was unexpected. Neuropathic pain has Fuc IV [9] present in addition to Fuc I and III whereas the noiceptive cases have Fuc II as well as Fuc I and III. Two cases of TN have been examined and increased glutamatergic dysfunction recorded as well as the appearance of Fuc IV. Fucose I and III were recorded in the control cohort but not Fuc II or Fuc IV. Free fucose was also recorded in most chronic pain cases.
CP/CPPS and IBS are often accompanied by “associated negative cognitive, behavioral or emotional” consequences. Fucose-α(1-2)-galactose [Fucα(1-2)Gal] sugars are implicated in the mechanisms that underlie neuronal development, learning, and memory [17]. The increase in free fucose and in the fucosylated epitopes associated in the early events of inflammation [18, 19] may affect the equilibrium and thus behavior and mental capacity. [18, 19] [20, 21].
Chronic prostatitis/chronic pelvic pain syndrome as used herein is defined as “urologic pain or discomfort in the pelvic region, associated with urinary symptoms and/or sexual dysfunction, lasting for at least 3 of the previous 6 months” in the absence of any identifiable pathology such as cancer, culturable infection, or anatomic abnormalities, often accompanied by “associated negative cognitive, behavioral, sexual or emotional consequences.
Neurochemical changes were found to occur in the brain of patients with CP/CPPS (
The 2D COSY method identified the fucose region as being diagnostic for CP/CPPS. This spectral region, is significantly increased (P<0.05) by 21% averaged over patients with CP/CPPS (
One can use a Siemens research clinical scanner, the PRISMA. The system has a 64 channel head and neck coil. We showed during a repetitive head injury study that the 32 channel gave reproducibility to 3% in contrast to the 12 channel of 8%.
In summary, neuro 2D MRS monitors alterations to neurochemical pathways associated with chronic pain and inflammation. One can determine the effects of upward (sensory neural connections) resulting in chronic pain and inflammation; and downward (motor and regulatory) neural connections on gut function.
One can collect 1D MRS data and analyze using the modern informatics to generate objective diagnostic tests for chronic pain from different origins.
Using 2D MRS data one can assign the diagnostic molecules and identify the neurochemical pathways that alter with each type of chronic pain.
One can also monitor the effect of therapy on patients with chronic pain. The spectral information can be analyzed and compared with the clinical outcomes. The effects of therapy and levels of pain can also be analyzed by modern informatics such as that discussed in U.S. Pat. No. 6,835,572 or U.S. Pat. No. 7,676,254.
All MR data can be acquired on a Siemens 3T Prisma using a 64 channel head and neck coil. The Prisma has double the current gradient strength (80 milli tesla per meter (mT/m) and a slew rate of 200 tesla per meter per second (T/m/s)), high order shims. The VD13D operating software incorporates the automated shim routine and capacity to control the water suppression [26].
Before undergoing spectroscopy, patients can be imaged with an MR imaging protocol that includes T2-weighted three-dimensional turbo spin-echo imaging with variable flip angle (repetition time=3.2 seconds, echo time=494 msec, section thickness=0.9 mm). Localized shimming can be performed with automatic adjustment of first- and second order shim gradients by using the automatic three-dimensional B 0 field mapping technique (Siemens) to achieve a magnitude peak width of water at half maximum resonance height of 14 Hz or less. After frequency adjustment, water-selective suppression can optimized by the VD13D software.
Single voxel short echo (TR/TE: 1500/30 ms, PRESS, voxel size: 2×2×2 cm3, 96 averages) can be acquired in; 1) prefrontal cortex; 2) parietal white matter, and 3) anterior white matter. Scan time can be 5 minutes per voxel.
A two-dimensional Correlated SpectroscopY (2D COSY) can be acquired in chosen brain regions with the following parameters: RF carrier frequency at 2.0 ppm; TR 1.5 s; weak water suppression using WET; spectral width of 2000 Hz; increments size of 0.8 ms in 64 t1 increments giving an indirect spectral width of 1250 Hz; 8 averages per increment; and 1024 data points. Scan time for the 2D COSY can be 11 minutes.
Structural imaging can be obtained with T1-weighted MPRAGE volumetric sequence (TR/TE=2530/1.7 ms, 12 degree flip angle, FOV=256×256 mm, voxel size 1×1×1 mm, NEX 4, acquisition time 6 minutes).
Diffusion tensor imaging (DTI) can consist of a 35-direction scan (TR/TE=9880/88 ms; FOV=256×256 mm; 2 mm slice thickness with 2×2 mm2 in-plane resolution; b-value=0 and 1000 s/mm2) for a scan time of 6 minutes.
Susceptibility Weighted Imaging (SWI) data can be acquired using the following parameters: TR/TE=28/20 ms, FOV 256×256 mm, 1 mm slice thickness with 1×1 mm2 in-plane resolution for a scan time of 6 minutes.
Quality control (Q/C) for MM and MRS data can be maintained by weekly phantom scans using both imaging and spectroscopy-specific phantoms.
In place of 2D COSY analysis, the 1D raw spectra of COSY can be concatenated into a two-dimensional array using Matlab. A Felix-2007 package (Accelrys, San Diego, Calif., USA) can be used for spectral processing and analysis[9]. The in vivo 2D spectra can be referenced to the prominent singlet diagonal peak of creatine Cr (F2=F1=3.02 ppm). Crosspeak and diagonal volumes can be measured as described in Lean et al Biochemistry. Felix-2007 processing software can provide the peak volumes of metabolite ratios in reference to Cr.
Statistical t-tests can be used to compare IBS groups and controls. In addition, multiANOVA statistical tests can be conducted to examine relationships between the MRI/MRS metrics and the PCSS, ImPACT, and balance error test scores. At follow-up, mean of groups as well as ratio of second to first scan for each individual can be compared.
The documentation of specific biochemical changes e.g., increases in excitatory amino acids; fucose (inflammation) can provide targets for pharmacological interventions going forward.
A preferred embodiment has been disclosed as one way of practicing the invention, but the invention is not limited to this embodiment. The scope of the invention is determined only by way of the following claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US15/21312 | 3/18/2015 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61955048 | Mar 2014 | US |
