Functional Imaging Markers Research Articles

Brain structure, function, and neurochemistry in schizophrenia and bipolar disorder\u2014a systematic review of the magnetic resonance neuroimaging literature

Since Emil Kraepelin’s conceptualization of endogenous psychoses as dementia praecox and manic depression, the separation between primary psychotic disorders and primary affective disorders has been much debated. We conducted a systematic review of case–control studies contrasting magnetic resonance imaging studies in schizophrenia and bipolar disorder. A literature search in PubMed of studies published between January 2005 and December 2016 was conducted, and 50 structural, 29 functional, 7 magnetic resonance spectroscopy, and 8 combined imaging and genetic studies were deemed eligible for systematic review. Structural neuroimaging studies suggest white matter integrity deficits that are consistent across the illnesses, while gray matter reductions appear more widespread in schizophrenia compared to bipolar disorder. Spectroscopy studies in cortical gray matter report evidence of decreased neuronal integrity in both disorders. Functional neuroimaging studies typically report similar functional architecture of brain networks in healthy controls and patients across the psychosis spectrum, but find differential extent of alterations in task related activation and resting state connectivity between illnesses. The very limited imaging-genetic literature suggests a relationship between psychosis risk genes and brain structure, and possible gene by diagnosis interaction effects on functional imaging markers. While the existing literature suggests some shared and some distinct neural markers in schizophrenia and bipolar disorder, it will be imperative to conduct large, well designed, multi-modal neuroimaging studies in medication-naïve first episode patients that will be followed longitudinally over the course of their illness in an effort to advance our understanding of disease mechanisms.

Abstract 4248: Functional imaging markers for blockade of breast cancer metastasis by IGF1R and insulin receptor targeted drugs using novel MRI and targeted iron oxide nanoparticles

Abstract IGF1R and insulin receptor (IR) regulate biology of estrogen positive (ER+) and triple negative breast cancer (TNBC) cells. The results of initial clinical trials with anti-IGF1R drugs have been disappointing due to feedback upregulation of insulin receptor (IR) signaling and absence of biomarkers for these drugs. We evaluated the effects of BMS-754807, a dual tyrosine kinase inhibitor of IGF1R/IR on ER+ and TNBC. In ER+ MCF-7 cells, it inhibited xenograft growth of MCF-7 tumors (n = 10 per treatment) compared to vehicle. Interestingly, while tumor growth was suppressed over a period of five weeks, eventually the tumors displayed resistance to BMS-754807. In TNBC, it inhibited motility in vitro. In contrast to ER+ cells, BMS-754807 did not inhibit primary tumor growth of TNBC cells injected into the mammary fat pad of mice. But at a dose of 50 mg/kg daily inhibited metastasis of TNBC cells, MDA-231-LM2 and MDA-MB435A/LCC6 cells, in the orthotopic and tail vein models of metastasis compared to vehicle (n = 10/group). Our data indicate that regulation of metastasis and tumor growth by IGF1R can be discrete events and functional imaging to identify biological properties of metastatic breast cancer regulated by IGF1R/IR are needed to better define treatments. While MRI is a powerful tool for detecting and imaging cancer, its utility in imaging metastasis to the lung is limited due to the challenges of lung MRI with conventional 3D gradient echo (GRE). MRI does not visualize lung well, mainly due to the abundance of air-tissue interfaces, which cause the MR signal to decay too rapidly for conventional MRI pulse sequences to capture. Clinically metastases are monitored by CT or PET but exposure of patients to ionizing radiation is a concern and problematic in longitudinal studies monitoring response to a targeted drug. Therefore, we recently reported the utility of a novel MR sequence called sweep imaging with Fourier transformation (SWIFT), where the data is acquired quasi-simultaneously with the radiofrequency pulse, to image lung metastasis of breast cancer. Here, we monitored response to IGF1R and IGF1R/IR targeted drugs in preclinical models of lung metastasis of breast cancer. We used MDA-231-LM2 cells with the tail vein injection model of metastasis. Mice with breast cancer metastases in the lungs were treated with either huEM164, an antibody against IGF1R, or BMS-754807. Metastasis was monitored by BLI and SWIFT MRI weekly. SWIFT was more sensitive in detecting inhibition of metastasis by these drugs. Thus, dual inhibition of IGF1R and IR is effective in blocking growth of ER+ and metastasis of TNBC. However, combination of this therapeutic strategy with other agents may be necessary to prevent or delay onset of resistance. Further, noninvasive biomarkers of response to IGF1R/IR targeted drugs can be developed with SWIFT imaging. Citation Format: Deepali Sachdev, Huy Donguyen, Naoharu Kobayashi, Sidath C. Kumarapperuma, Joeseph C. Weber. Functional imaging markers for blockade of breast cancer metastasis by IGF1R and insulin receptor targeted drugs using novel MRI and targeted iron oxide nanoparticles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4248.

An early Alzheimer's disease functional imaging marker: Olfactory deficits in Alzheimer's disease and MCI reflect degeneration of central olfactory system

An early Alzheimer's disease functional imaging marker: Olfactory deficits in Alzheimer's disease and MCI reflect degeneration of central olfactory system

An early Alzheimer's disease functional imaging marker: Olfactory deficits in Alzheimer's disease and MCI reflect degeneration of central olfactory system

An early Alzheimer's disease functional imaging marker: Olfactory deficits in Alzheimer's disease and MCI reflect degeneration of central olfactory system

The role of sexual abuse on functional neuroimaging markers associated with major depressive disorder

Objectives. Victims of child sexual abuse can develop depression and other mental health conditions that follow them well into adulthood. This study aimed to clarify the role of sexual abuse (SA) on functional imaging markers associated with MDD. Methods. Thirty-seven patients with MDD only; and 13 patients with both MDD and SA and 43 healthy controls performed emotional attention shifting tasks during fMRI session. Clinical diagnoses were made by consultant psychiatrists based on the DSM-IV-TR criteria and diagnoses were confirmed using SCID-I. Magnetic resonance images were obtained with a Philips Achieva 3 Tesla MRI scanner. Short form childhood trauma questionnaire, Hamilton Rating Scale for Depression and Beck's Depression Inventory were also employed. Data were analysed with Statistical Parametric Mapping 8 (SPM8). Results. Using the contrast judgment of emotion minus judgment of geometry following emotional neutral stimuli, patients with MDD showed significantly reduced activation in comparison to healthy controls in the area of the right fusiform gyrus. With the contrast judgment of emotion minus judgment of geometry following emotional negative stimuli, participants with MDD and SA showed significantly higher activation in the area of the left inferior parietal lobe in comparison to participants with MDD without SA. Conclusions. The history of sexual abuse affects functional neuroimaging markers associated with major depressive disorder.

OC-0019: The role of functional imaging and molecular markers for organ-preserving strategies after CRT for rectal cancer

Results: The number of responders was 145 (45%) and 28 (49%), for the training and validation cohort, respectively. Feature space reduction resulted in a set of 34 highly robust and non-redundant features and subsequent model development lead to a multivariable model consisting of 8 features (Table 1) with an out-of-sample AUC of 0.63±0.09. Independent validation resulted in an AUC of 0.77. Model derived ROC curves for both the training and validation cohort and overall AUC values are shown in Figure 1b.

Emotional Processing Functional Magnetic Resonance Imaging Is Associated with Treatment Response in Late Life Depression

Late-life depression (LLD) is a distinct clinical entity which has been estimated to affect 8-16% of elderly patients. Its disease burden is considerable with effects on mortality, development of dementia, functional status, and healthcare utilization. Research has established functional magnetic resonance imaging (fMRI) markers as reliable predictors of treatment in response in LLD, including differential activity and connectivity between various neural structures and networks. However, an underexplored area of previous fMRI studies is whether neural activity during affective tasks may be associated with treatment response in LLD.

SU-E-J-215: Onboard Split PET Including the Effects of Attenuation, Scatter, and Random Events

Purpose: Positron emission tomography (PET) using split PET geometry was investigated as an on-board system for functional imaging and PET marker tracking, specifically with tomotherapy. The open dual ring PET would allow measurement of both inter and intra-fractional variation, improving the delineation of tumor volume at any stage in the radiation treatment delivery process. We present results from data obtained using Monte Carlo simulations including the effects of attenuation, random events, and scatter. Methods: PET design was accomplished via Monte Carlo simulations with GATE, the Geant4 Application for Emission Tomography. Images were reconstructed using Software for Image Reconstruction (STIR) with a fully 3D ordered subset expectation maximization (OSEM) image reconstruction technique. Results: Monte Carlo simulations of the split PET geometry indicate that including physical factors that degrade image quality such as attenuation, random events, and scatter still prove the feasibility of near real-time PET for both inter and intra-fractional radiation delivery. The image quality of scan times under 1 minute reveals that it is possible to utilize PET scanning and reconstruction during the treatment session intrafractionally. GATE also simulates the depth information but does not correct obliqueness of the path of line of response so the data is much moremore » realistic than the data obtained with ray tracing. Conclusion: Onboard split PET with TomoTherapy can generate quality images under 1 minute scan times without the need to correct for attenuation, scatter, random events, or depth information of the interaction.« less

MRI assessment of cerebral oxygen metabolism in cocaine-addicted individuals: hypoactivity and dose dependence.

Long-term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task-evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural-activity-specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine-addicted subjects and 13 age- and gender-matched control subjects, and examined the impact of long-term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine-addicted subjects (152 ± 16 µmol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 ± 20 µmol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine-addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long-term effects of cocaine use on the brain.

Correlations between Functional Imaging Markers Derived from PET/CT and Diffusion-Weighted MRI in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

ObjectivesTo investigate the correlations between functional imaging markers derived from positron emission tomography/computed tomography (PET/CT) and diffusion-weighted magnetic resonance imaging (DWI) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Further to compare the usefulness of these tumor markers in differentiating diagnosis of the two common types of Non-Hodgkin's lymphoma (NHL).Materials and MethodsThirty-four consecutive pre-therapy adult patients with proven NHL (23 DLBCL and 11 FL) underwent PET/CT and MRI examinations and laboratory tests. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and metabolic tumor burden (MTB) were determined from the PET/CT images. DWI was performed in addition to conventional MRI sequences using two b values (0 and 800 s/mm2). The minimum and mean apparent diffusion coefficient (ADCmin and ADCmean) were measured on the parametric ADC maps.ResultsThe SUVmax correlated inversely with the ADCmin (r = −0.35, p<0.05). The ADCmin, ADCmean, serum thymidine kinase (TK), Beta 2-microglobulin (B2m), lactate dehydrogenase (LD), and C-reactive protein (CRP) correlated with both whole-body MTV and whole-body MTB (p<0.05 or 0.01). The SUVmax, TK, LD, and CRP were significantly higher in the DLBCL group than in the FL group. Receiver operating characteristic curve analysis showed that they were reasonable predictors in differentiating DLBCL from FL.ConclusionsThe functional imaging markers determined from PET/CT and DWI are associated, and the SUVmax is superior to the ADCmin in differentiating DLBCL from FL. All the measured serum markers are associated with functional imaging markers. Serum LD, TK, and CRP are useful in differentiating DLBCL from FL.

The NINDS Stroke Progress Review Group Final Analysis and Recommendations

As the nation’s primary supporter of basic and clinical stroke research, the National Institute of Neurological Disorders and Stroke (NINDS) strives to pursue the most pressing and promising scientific opportunities. During the past decade, NINDS has led a stroke planning effort performed by the Stroke Progress Review Group (PRG), an external group of prominent stroke scientists, clinicians, and consumer advocates.1 The third report of the Stroke PRG, summarized here, was posted in January 2012.2 It is the product of ≈200 stroke experts working in 16 topic-related workgroups and provides a comprehensive view of stroke research advances, challenges, and scientific opportunities. The Stroke PRG reports serve to inform the research community and funding agencies, including the National Institutes of Health that invests more than $300 million annually in stroke research. In 2012, the NINDS used the Stroke PRG report as the foundation for engaging the global stroke community in building consensus around the highest stroke research priorities. Short summaries and 2 to 3 research priorities from each workgroup follow, and bulleted versions of the priorities are listed in Table 1. The topics are ordered loosely from basic to clinical research, although many of the recommendations are crosscutting and overlapping. ### Imaging Neuroimaging is now being used for selection, monitoring, and testing of different therapeutic interventions. Identification of penumbral tissue using both MRI and computed tomographic techniques has markedly advanced. Functional imaging markers are also being developed, which could advance our knowledge of the underlying mechanisms of brain injuries and serve as surrogate outcomes for clinical trials. New molecular and cellular neuroimaging technologies are being used to define pathophysiological mechanisms. From a practical standpoint, the most cost-effective imaging workup for patients with both ischemic stroke and intracerebral hemorrhage, based on which modalities lead to treatment decisions that have been proven to …

MEG Delta Mapping Along the Healthy Aging-Alzheimer's Disease Continuum: Diagnostic Implications

New diagnostic criteria for Alzheimer's disease (AD) stress the role of in vivo biomarkers. Neurophysiological markers are usually not considered as such criteria, although theoretical and practical reasons would justify them. In order to assess the value of neurophysiology as an AD biomarker, whole-head magnetoencephalographic (MEG) resting state recordings were obtained from 35 AD patients, 23 mild cognitive impairment (MCI) patients, and 24 healthy controls. The AD group was further split into two groups differing in severity according to the GDS/FAST criteria. A Minimum Norm Estimation procedure was utilized to estimate the cortical origin of slow brain oscillatory activity in the delta band (2-4 Hz). Eight regions of interest (ROIs) discriminated between AD patients and controls. Delta current density (DCD) in all ROIs showed a significant negative correlation with cognitive status (p < 0.001). DCD values in posterior parietal, occipital, prerolandic, and precuneus cortices distinguished reliably between MCI patients, AD patients with different severity scores, and controls. Importantly, an increase of DCD in right parietal cortex and precuneus indexed the transition from MCI to mild dementia and from mild to more severe dementia. MEG delta mapping might be a serious candidate for a "neural degeneration" marker of AD reflecting dysfunctional synaptic transmission. More importantly, the localization of DCD values is in line with functional imaging markers of AD. However, MEG delta mapping is a totally non-invasive technique that directly measures neural activity. We propose that individuals with enhanced DCD in posterior parietal and precuneus cortices are at risk of progression to full dementia.

Somatosensory evoked changes in cerebral oxygen consumption measured non-invasively in premature neonates

The hemodynamic functional response is used as a reliable marker of neuronal activity in countless studies of brain function and cognition. In newborns and infants, however, conflicting results have appeared in the literature concerning the typical response, and there is little information on brain metabolism and functional activation. Measurement of all hemodynamic components and oxygen metabolism is critical for understanding neurovascular coupling in the developing brain.To this end, we combined multiple near infrared spectroscopy techniques to measure oxy- and deoxy-hemoglobin concentrations, cerebral blood volume (CBV), and relative cerebral blood flow (CBF) in the somatosensory cortex of 6 preterm neonates during passive tactile stimulation of the hand. By combining these measures we estimated relative changes in the cerebral metabolic rate of oxygen consumption (rCMRO2).CBF starts increasing immediately after stimulus onset, and returns to baseline before blood volume. This is consistent with the model of pre-capillary arteriole active dilation driving the CBF response, with a subsequent CBV increase influenced by capillaries and veins dilating passively to accommodate the extra blood. rCMRO2 estimated using the steady-state formulation shows a biphasic pattern: an increase immediately after stimulus onset, followed by a post-stimulus undershoot due to blood flow returning faster to baseline than oxygenation. However, assuming a longer mean transit time from the arterial to the venous compartment, due to the immature vascular system of premature infants, reduces the post-stimulus undershoot and increases the flow/consumption ratio to values closer to adult values reported in the literature.We are the first to report changes in local rCBF and rCMRO2 during functional activation in preterm infants. The ability to measure these variables in addition to hemoglobin concentration changes is critical for understanding neurovascular coupling in the developing brain, and for using this coupling as a reliable functional imaging marker in neonates.

Du laboratoire vers la clinique : expérience du glioblastome pour moduler la radiosensibilité tumorale

Despite significant progress in the treatment of glioblastoma, the prognosis of these radioresistant, invasive and hypoxic tumours remain dark. The constant relapse after treatment of this tumour is in part due to its intra-cellular but also micro-environmental radioresistance, largely controlled by growth factors and their receptors. The complexity of the biology of these tumours and the presence of numerous cross-talks between the pathways of these different growth factors can be in part responsible for the negative results obtained in clinical trials associating radiotherapy and targeted drugs designed without previous in vitro and in vivo studies validating the proof of concept of a specific target as key factor of radioresistance. In the aim to optimize the treatment of glioblastoma and to reduce the risks of failure of new trials, several laboratories and clinical departments are developing translational research in radiotherapy and radiobiology, validating in vitro and then in orthotopic xenografts interesting targets, then studying the radiosensitizing effect of targeted drugs directed against these proteins, studying the mechanisms of action and resistance of these drugs, validating these proteins as predictive factors of response to radiotherapy in the patients, and then designing clinical trials, integrating metabolic or functional imaging and surrogate markers to better understand the mechanism of action of these associations. We describe in this article the main translational research axis developed for radiosensitizing glioblastoma, which our lab and department have pursued for several years.

TU‐C‐214‐12: On‐Board PET with Tomotherapy Using Open Dual Ring Geometry with Consideration to DOI Effect

Purpose: Positron emission tomography (PET) using open dual ring geometry was investigated as an on‐board system for functional imaging and PET marker tracking, specifically with tomotherapy. The open dual ring PET would allow measurement of both inter and intra‐fractional variation, improving the delineation of tumor volume at any stage in the radiation treatment delivery process. We compare results from data obtained with ray tracing to data from Monte Carlo simulations. This study demonstrates that depth of information (DOI) along the z axis of the crystal is required to reduce artifact from DOI blurring due to long axial PET geometry. Methods: PET design was accomplished via Monte Carlo simulations with GATE, the Geant4 Application for Emission Tomography. Images were reconstructed using Software for Image Reconstruction (STIR) with a fully 3D OSEM. Investigation of whether the image blurring is the result of DOI was carried out by scaling axially the PET design to one half and one forth the original proposed open PET. Image reconstruction with varying the ring difference or level of obliqueness of the accepted lines of response (LORs) for reconstruction also indicates the role of the DOI blurring. Results: Monte Carlo simulations of the open PET geometry indicate that the prominent physical factor that degrades image quality is the DOI. When comparing the Monte Carlo simulation for a phantom with four hot sources and cold background in air (reducing the effect of attenuation, randoms, and scatter) to that of the ray tracing simulations, we can visualize the degradation in the image quality. The reason is that GATE simulates the depth information but does not correct for DOI blurring, but STIR generated data assumes all LORs interact at the crystal surface. Conclusions: Onboard open PET with Tomotherapy must include DOI detectors to correct for the observed blurring.

MO‐E‐204C‐03: On the Development of On‐Board PET with Tomotherapy Using Open Dual Ring Geometry

Purpose: Positron emission tomography (PET) using open dual ring geometry was investigated as an on‐board system for functional imaging and PET marker tracking, specifically with tomotherapy. The dual ring PET would allow measurement of both inter and intra‐fractional variation, facilitating the determination of treatment uncertainties and improving the delineation of tumor volume at any stage in the radiation treatment delivery process. This study demonstrates the field of view (FOV) of various PET ring axial gaps, the sensitivity of each system for each gap, and the image quality as a function of scan time and activity for one specified design. Method and Materials: Investigation of FOV and sensitivity of each design was accomplished via Monte Carlo simulations with GATE, the Geant4 Application for Emission Tomography. Image quality was investigated with a fully 3D OSEM iterative reconstruction algorithm for noiseless data to investigate the FOV and noisy data to investigate the scan time at a specified activity. Results: Even when the axial gap (G) exceeded the axial width (W) for each open ring system as in the extreme case of G = 600 mm (required to avoid actuators holding MLC's) the axial FOV was approximately 200 mm. A continuous axial and transaxial FOV (determined by PET ring diameter) of 360 mm and 450 mm respectively resulted from G=W=120mm. Reconstructed NEMA 2001 phantom images for activity of 15 mCi/70kg and scan times ranging from 10 to 100 seconds was demonstrated without the effect of attenuation, scatter, and random events. `Conclusion: For tomotherapy treatment 200 mm continuous FOV axially was sufficient and was achievable with all gaps simulated in the range from 120 mm to 600 mm. Open dual ring on‐board PET has the potential to acquire images within the time limit of a tomotherapy treatment session.

14th International Headache Congress: Basic Science Highlights

During the 14th International Headache Congress the results of several innovative studies that contribute to our understanding of headache pathophysiology and treatment were presented. Here we summarize work expected to contribute substantially to understanding headache mechanisms, while an accompanying manuscript summarizes presentations regarding the treatment of headache. This manuscript highlights research on mechanisms of photophobia and phonophobia, pharmacologic inhibition of cortical spreading depression, a proposed mechanism by which oxygen effectively treats cluster headache, identification of functional and structural aberrations in people with hypnic headache, and research on functional imaging markers of a migraine attack.

Test–retest reproducibility of the default‐mode network in healthy individuals

Independent component analysis (ICA) of functional magnetic resonance imaging (fMRI) time-series reveals distinct coactivation patterns in the resting brain representing spatially coherent spontaneous fluctuations of the fMRI signal. Among these patterns, the so-called default-mode network (DMN) has been attributed to the ongoing mental activity of the brain during wakeful resting state. Studies suggest that many neuropsychiatric diseases disconnect brain areas belonging to the DMN. The potential use of the DMN as functional imaging marker for individuals at risk for these diseases, however, requires that the components of the DMN are reproducible over time in healthy individuals. In this study, we assessed the reproducibility of the DMN components within and between imaging sessions in 18 healthy young subjects (mean age, 27.5 years) who were scanned three times with two resting state scans during each session at 3.0 T field strength. Statistical analysis of fMRI time-series was done using ICA implemented with BrainVoyager QX. At all three sessions the essential components of the DMN could be identified in each individual. Spatial extent of DMN activity and size of overlap within and between sessions were most reproducible for the anterior and posterior cingulate gyrus. The degree of reproducibility of the DMN agrees with the degree of reproducibility found with motor paradigms. We conclude that DMN coactivation patterns are reproducible in healthy young subjects. Therefore, these data can serve as basis to further explore the effects of aging and neuropsychiatric diseases on the DMN of the brain.

A Markov decision process approach to temporal modulation of dose fractions in radiation therapy planning

The current state of the art in cancer treatment by radiation optimizes beam intensity spatially such that tumors receive high dose radiation whereas damage to nearby healthy tissues is minimized. It is common practice to deliver the radiation over several weeks, where the daily dose is a small constant fraction of the total planned. Such a ‘fractionation schedule’ is based on traditional models of radiobiological response where normal tissue cells possess the ability to repair sublethal damage done by radiation. This capability is significantly less prominent in tumors. Recent advances in quantitative functional imaging and biological markers are providing new opportunities to measure patient response to radiation over the treatment course. This opens the door for designing fractionation schedules that take into account the patient's cumulative response to radiation up to a particular treatment day in determining the fraction on that day. We propose a novel approach that, for the first time, mathematically explores the benefits of such fractionation schemes. This is achieved by building a stylistic Markov decision process (MDP) model, which incorporates some key features of the problem through intuitive choices of state and action spaces, as well as transition probability and reward functions. The structure of optimal policies for this MDP model is explored through several simple numerical examples.

SU-FF-T-170: A Markov Decision Process Approach to Temporal Modulation of Dose Fractions in Radiotherapy Planning

Purpose: To use a Markov Decision process to explore the possibility of using non‐constant adaptive fractionation schedules by incorporating the patient's cumulative response in optimizing the size of a fraction during the specified time period. Method and Materials: Our method anticipates that advances in functional imaging and biological markers will soon enable us to observe the patient's response to radiation during a course of treatment. A stylistic Markov Decision Process model which incorporates key features of the problem through intuitive choices of state and action spaces, as well as transition probability and reward function is built. We first formulate the problem over a finite horizon by fixing the number of treatment sessions a priori. The optimal fraction size is determined by solving Bellman's equation through backward induction to maximize the expected total reward. Then the model is extended to an infinite horizon where the optimal stopping point (termination of the treatment) is found through value iteration algorithms. In case it is optimal to continue, the optimal size of fractional dose is determined by maximizing the expected total reward for the entire treatment course. Results: Monotone optimal policy for the finite horizon formulation has been observed i.e. if dosed is optimal in organ state s, then a dose at least as big as d is optimal when the organs at risk/tumors are better/worse than states. Conclusion: We have taken initial steps to temporally modulated radiotherapy by exploiting radio‐biological information available through advances in quantitative imaging modalities. As a result, this opens the door for including patient specific responses in designing treatment plans.