JP2018100923A - Light irradiation device, light irradiation method and light irradiation program - Google Patents

Abstract

PROBLEM TO BE SOLVED: To cause light to be focused by high enhancement depending on a desired position as in the inside of a medium, etc.SOLUTION: A light irradiation device comprises: spatial light modulation means 107 for modulating light from a light source 100 and forming a wavefront of the light; an optical system 108 for irradiating a medium with the light having had the wavefront formed; detection means 110 for detecting a signal generated from the medium irradiated with the light; and control means 111 for carrying out an optimization process for causing a wavefront to be formed by the spatial light modulation means so that the strength of a signal detected in the inside of the medium or at an external detection position. The control means acquires a strength distribution of the signal in a prescribed region that includes the detection position, carries out a correction process for correcting the detection position or the signal on the basis of the strength distribution, and carries out an optimization process so that the strength of the signal after the correction process increases.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a technique for imaging by irradiating a medium with light.

  When imaging optical properties inside a medium such as a living body using non-infrared or near-infrared light from the visible range, the wavefront of the light incident on the medium is shaped appropriately, thereby shaping the light. It is possible to efficiently reach the position inside or behind the medium. Non-Patent Document 1 discloses a method of shaping an incident wavefront with a spatial light modulator (SLM) so that the intensity of transmitted light at a specific position increases when irradiating light to a scattering medium. ing. Patent Document 1 discloses a method of using a photoacoustic signal as a wavefront optimization target instead of transmitted light. Further, Non-Patent Document 2 discloses a method for targeting a fluorescence signal (TPF: Two-photon fluorescence) by two-photon absorption.

  In this way, various signals are used as targets for shaping the wavefront, and by appropriately shaping the wavefront of the light incident on the scattering medium, the light can be placed in a desired position inside or behind the scattering medium. Can be focused. And by increasing the intensity of the signal (transmitted light, fluorescence, photoacoustic signal, etc.) at the position where the light is focused, the penetration depth of imaging targeting various scattering media including biological tissue is improved. Can be made. Further, the SNR (Signal-to-Noise Ratio) of imaging can be improved.

US Patent Publication No. 2011/0083509

I. M. Vellekoop and A. P. Mosk, “Focusing coherent light through opaque strongly scattering media”, Optics Letters Vol.32, No.16 2309-2311 (2007) Jianyong Tang, Ronald N. Germain and Meng Cui, Superpenetration optical microscopy by iterative multiphoton adaptive compensation technique ”, Proceeding of the National Academy of Sciences USA, 109 (22) 8434-8439 (2012)

  In the wavefront shaping method as described above, the signal intensity of transmitted light or the like is monitored as a feedback signal at a specified position. For example, a signal that changes following the modulation of the phase of light incident on the medium by the SLM is monitored, and the phase (optimum phase) when the intensity of the signal is maximized is set in the SLM. However, there are cases where the phase cannot be measured with high accuracy due to the influence of noise, and in this case, the light intensity increasing effect (enhancement) is reduced.

  The present invention provides a light irradiation device and the like that can focus light with high enhancement at a desired position such as the inside of a medium.

  A light irradiation apparatus according to one aspect of the present invention includes a spatial light modulation unit that modulates light from a light source to shape a wavefront of the light, an optical system that irradiates a medium with light having the wavefront, Control for performing detection processing for detecting a signal generated from the irradiated medium and optimization processing for shaping the wavefront in the spatial light modulation means so as to increase the intensity of the signal detected at a detection position inside or outside the medium. Means. Then, the control means acquires the intensity distribution of the signal in a predetermined region including the detection position, performs a correction process for correcting the detection position or signal based on the intensity distribution, and increases the intensity of the signal after the correction process. The optimization process is performed as described above.

  A light irradiation method according to another aspect of the present invention includes a spatial light modulation unit that modulates light from a light source to shape a wavefront of the light, an optical system that irradiates a medium with light having the wavefront formed thereon, and Optimizing the step of providing a detection means for detecting a signal generated from a medium irradiated with light and causing the spatial light modulation means to shape the wavefront so that the intensity of the signal detected at the detection position inside or outside the medium increases. And a control step for performing the conversion process. Then, in the control step, a signal intensity distribution in a predetermined region including the detection position is acquired, and a correction process for correcting the detection position or signal based on the intensity distribution is performed, and the intensity of the signal after the correction process is increased. The optimization process is performed as described above.

  In addition, the light irradiation program as a computer program which makes a computer perform the process according to the said light irradiation method also comprises the other one side of this invention.

According to the present invention, it is possible to focus light with high enhancement at a detection position such as the inside of a medium.

1 is a diagram illustrating a configuration of an imaging apparatus that is Embodiment 1 of the present invention. FIG. 5 is a flowchart showing an optimization process for incident wavefronts according to the first embodiment. FIG. 3 is a diagram illustrating an intensity distribution of transmitted light before wavefront optimization processing in the first embodiment. The figure which plotted the signal intensity | strength in the target position in Example 1 as a function of the frequency | count N of repetition in an optimization process. FIG. 3 is a diagram illustrating an initial target position and a corrected target position in the first embodiment. FIG. 6 is a diagram illustrating a configuration of an imaging apparatus that is Embodiment 2 of the present invention. FIG. 6 is a schematic diagram showing a processing flow in Embodiment 2. FIG. 10 is a diagram illustrating signal correction at an initial target position in the second embodiment. FIG. 10 is a diagram illustrating imaging performed by scanning a focus position in the second embodiment. FIG. 6 is a diagram illustrating a configuration of an imaging apparatus that is Embodiment 3 of the present invention. FIG. 10 is a diagram illustrating an initial target position and a corrected target position in the third embodiment.

  Embodiments of the present invention will be described below with reference to the drawings.

  FIG. 1 shows the configuration of an imaging apparatus as a light irradiation apparatus that is Embodiment 1 of the present invention. The light source 100 is a laser light source that emits continuous light (CW light) having a wavelength in the visible region to the near infrared region such as 400 to 1500 nm and having a constant intensity over time. The wavelength of the light source 100 can be arbitrarily set according to the purpose of use of the light irradiation device. The light source 100 may emit intensity-modulated light or pulsed light.

  The light emitted from the light source 100 is converted into parallel light by the spatial filter 101 and the lens 102, the beam size is appropriately adjusted by the variable aperture 103, and the light intensity is appropriately adjusted by the ND filter 104. Instead of using the ND filter 104, the light intensity may be adjusted by directly changing the output of the light source 100. The beam size is adjusted with reference to an effective area of a spatial light modulator (SLM) 107 described later.

  The light 120 whose beam size and light intensity are adjusted passes through the beam splitter (BS) 106 and enters the SLM 107. For example, LCOS (Liquid crystal On Silicon) can be used as the SLM 107. As the SLM 107, a reflective SLM or a transmissive SLM can be used as shown in FIG.

  The SLM 107 is connected to a personal computer (PC) 111 as control means and is controlled by the PC 111. A dedicated CPU or MPU may be used as the control means. The SLM 107 modulates (phase-modulates) the incident light 120 by a wavefront optimization process described later, and shapes the wavefront of the light. The polarization of the incident light 120 is adjusted so as to coincide with the polarization direction in which phase modulation is performed by the SLM 107.

  The light 121 reflected by the SLM 107 and shaped in wavefront enters the sample 125, which is a medium, through the lens. At this time, the distance between the lens 108 and the SLM 107 and the distance between the lens 108 and the entrance surface of the sample 125 are all equal to the focal length of the lens 108. The incident surfaces of the SLM 107 and the sample 125 have a Fourier transform relationship. That is, the wavefront formed by the SLM 107 is Fourier-transformed and enters the sample 125. The sample 125 is a scattering medium for the incident light 121. For example, the sample 125 may be a living tissue or a medium such as a diffusion plate or a resin.

  Scattered light (optical signal) 122 that has passed through the sample 125 that is a scattering medium and exited the sample 125 passes through the lens 109 and is imaged by a CCD sensor (hereinafter simply referred to as a CCD) 110 as an imaging device. As the imaging device, a CMOS sensor, an area sensor having an image intensifier, EMCCD, sCMOS, or the like may be used. The CCD 110 is connected to and controlled by the PC 111. A monitor image acquired by imaging by the CCD 110 is transferred to the PC 111 and analyzed.

  Next, the wavefront optimization process will be described. In this process, first, the position of the signal to be monitored is set. Specifically, the user of this apparatus designates an arbitrary position in the monitor image as a target position (detection position). In the following description, the target position is specified behind the sample 125 (the position of the CCD 110), but may be specified inside the sample 125.

  Next, in this process, the phase of the SLM 107 is increased so that the intensity of the optical signal detected by the CCD 110 as the detecting means at the target position, that is, the intensity of the electric signal output from the CCD 110 (hereinafter referred to as signal intensity) increases. Modulate. By repeatedly performing this phase modulation, a focus spot is finally formed at the target position, and an effect of increasing the light intensity (enhancement) is obtained. The target position, in other words, the target area for monitoring the signal intensity can be set to an arbitrary size in units of the CCD 110 pixels. However, in order to increase the enhancement, the target position (target area) is preferably set to be equal to or smaller than the size of speckle grains observed by the CCD 110. The size of the speckle grain is determined by the aperture of the lens 109 and the arrangement of the sample 125, the lens 109, and the CCD 110, and can be adjusted to a desired size in the CCD 110.

  On the SLM 107, the incident light 120 is divided into a plurality of segments, and the wavefront of the incident light 120 is independently shaped (phase modulated) in each segment. Each segment includes a plurality of pixels of the SLM 107, and the size of the segment and the number N of segments (that is, the number of divisions of the incident wavefront) are appropriately set according to the purpose. If the number of segments N is increased, enhancement due to focus increases, but the number of measurement iterations also increases, so measurement time is required. The number of segments N is set in consideration of the balance between enhancement and measurement time.

  Next, the wavefront optimization process (S1200) will be described with reference to FIG. The PC 111 executes this processing according to a light irradiation program (light irradiation method) which is a computer program. In the following description and FIG. 2, S means a step.

  First, in S1221, the PC 111 selects a segment j (j = 1 to N) of the SLM 107. Here, the number of segments N is equal to the number of iterations of the wavefront optimization process for each segment described later. In S1222, the PC 111 confirms whether j is larger than the number of segments N (that is, the processing has been completed for all segments). If j> N, the processing is terminated. On the other hand, if j is still less than or equal to the number of segments N, the PC 111 proceeds to S1223.

In step S1223, the PC 111 measures (detects) the intensity of light transmitted through the target position through the CCD 110, and stores the signal value from the CCD 110 indicating the light intensity in the memory in the PC 111 together with the phase value φ _j of the segment j. Save as φ _j signal data.

Next, in S1224, the PC 111 determines whether or not the phase φ _j exceeds 2π. If not, the PC 111 proceeds to S1225 and updates the phase φ _j of the segment j by adding the phase Δφ (φ _j → φ _j + Δφ). The phase Δφ has a discretized phase step size and is set in consideration of measurement accuracy and speed. In step S1223, the PC 111 measures the light intensity at the target position again with respect to the updated phase φ _j and stores the φ _j signal data in the memory in the PC 111. Thus, the processes of S1225 and S1223 are repeated until the phase φ _{j of the} segment j exceeds 2π.

When the phase φ _j of the segment j exceeds 2π in S1224, the PC 111 proceeds to S1226, and from the φ _j signal data of the segment j stored in the memory, the optimum phase φ _{j_max} that maximizes the light intensity at the target position. Is read. The optimum phase φ _{j_max} is set as the phase of the segment j of the SLM 107.

  In step S1227, the PC 111 repeats the wavefront optimization process in steps S1222 to S1227 described above for the segment j + 1. By executing the wavefront optimization process for all the segments of the SLM 107 in this way, the wavefront of light from the SLM 107 toward the target position is optimized, and a focus spot can be formed at the target position. As the wavefront optimization processing, a partitioning algorithm that simultaneously optimizes a plurality of segments disclosed in Document A may be used instead of the above-described algorithm for optimizing the phase of each segment of the SLM. Further, as disclosed in Document B, a genetic algorithm can also be used.

(Reference A) IMVellekoop, AP Mosk, “Phase control algorithms for focusing light through turbid media”, Optics Communications 281 (2008) 3071-3080
(Reference B) Donald B. Conkey et al., “Genetic algorithm optimization for focusing through turbid media in noisy environments”, Optics Express Vol.20, No.5 (2012)
FIG. 3A shows a transmission image 130 observed through the CCD 110 before performing the wavefront optimization process. In the transmission image 130, the whiter the signal intensity, the higher the signal intensity, and the blacker the signal intensity, the lower. 131 and 132 are target positions. FIG. 3B shows a signal intensity distribution (one-dimensional cross section) 140 around the focus spot formed at the target positions 131 and 132 by the wavefront optimization process. Distribution 141 (Δ dotted line) and distribution 142 (+ solid line) in the figure are signal intensity distributions when set at target positions 131 and 132, respectively.

A distribution 143 (dotted line) is an average signal intensity distribution of the transmission image 130 before the wavefront optimization process is performed. FIGS. 3A and 3B show examples of signal intensity at the target position and enhancement at the formed focus spot. Before performing the wavefront optimization process, a position with a low signal intensity level such as the target position 132 is set as the target position, so that it is sensitive to the influence of noise generated by various factors of the apparatus. Therefore, a measurement error occurs in the measurement in S1223 of FIG. 2, and the optimum phase φ _{j_max} cannot be _obtained with high accuracy in _S1226 . As a result, as shown in the distribution 142 of FIG. 3B, the enhancement is lower than the distribution 141, and a difference occurs in the peak intensity at the focus spot. Thus, depending on the measured SNR, the enhancement of the focus finally formed is affected.

  The signal intensity at the target position 132 is lower than the average signal intensity around it, and is more susceptible to noise than the target position 131 whose signal intensity is equal to or greater than the average signal intensity. In the process of performing the iterative wavefront optimization process according to the flowchart of FIG. 2, the signal strength gradually increases at both the target positions 131 and 132, so that the SNR is gradually improved. However, at the initial stage in the wavefront optimization process, the signal intensity level is usually very weak and susceptible to noise. Therefore, at the initial stage of the wavefront optimization process, it is necessary to monitor the change in signal intensity at the target position due to the phase modulation of the SLM 107 with the best possible SNR.

FIG. 4 shows another example showing the effect of SNR on the measurement at the initial stage of the wavefront optimization process. This figure plots the signal strength at the target position as a function of the number of iterations of the wavefront optimization process. The signal strength 151 at the target position increases as the number of iterations N increases, and the signal strength increases even if the wavefront optimization process is repeated in the region 153 of the number of iterations exceeding the number of segments. The signal strength in the region 153 indicates the result when the wavefront optimization process is performed again after returning to the segment of j = 1 after the process for the segment j = N (S1222) is completed. The number of iterations indicated by this region 153 corresponds to the number of iterations required until the signal intensity increases from the initial state indicated by the region 152 to the average signal strength around. That is, in the repetition of the wavefront optimization process in the region 152, the desired phase φ _{j_max} is not obtained with sufficient accuracy. This is also a problem caused by the SNR described above.

  As can be seen from the above, by improving the SNR as much as possible in the initial stage of the wavefront optimization process, it is possible to efficiently improve the enhancement at the focus point without having to increase the number of extra iterations exceeding the number of segments N. Can do.

  In order to improve the SNR, it is advantageous that the signal intensity at the target position is large. For this reason, it is desirable to set the signal strength as high as possible as the initial signal strength in the wavefront optimization process.

  FIG. 5 is a transmission image observed by the CCD 110, and shows a transmission image of an area including the initial target position 201 and in the vicinity of the initial target position 201 (predetermined area: hereinafter referred to as a target vicinity area). The initial target position is arbitrarily set according to the purpose of use of the light irradiation apparatus of the present embodiment. For example, when imaging is performed using the light irradiation apparatus according to the present embodiment, an arbitrary point within a region of interest to be imaged may be set as the initial target position.

  In FIG. 5, the signal strength at the initial target position 201 is very small and lower than the average signal strength around it. On the other hand, speckle grains having a signal strength equal to or higher than the average signal strength exist at the positions 202 to 204.

  A range that is allowed even if the point at which the focus spot is formed is shifted in the horizontal direction (in the plane of the transmission image 200) with respect to the initial target position 201 is set as the target vicinity region 210. The size of the target vicinity area 210 is set based on the purpose of imaging and the like, the size of speckle grains, and the like. For example, the target vicinity region 210 is within 100 pixels in diameter with the initial target position 201 as the center.

  A signal intensity distribution is measured in the target vicinity area 210 and a threshold value (predetermined value) of the signal intensity is set, and a speckle grain having a signal intensity equal to or higher than the threshold value (predetermined value) is searched. For example, the speckle grain at the positions 202 and 203 is selected by setting the threshold value to the average signal intensity near the initial target position 201. The threshold may be higher than the average signal intensity near the initial target position 201.

  Then, a speckle grain position (specific position) 202 having a larger maximum signal intensity among the speckle grains at the selected positions 202 and 203 is selected as a new target position. At this time, an area that falls within an average speckle grain size centering on the position 202 where the signal intensity is the maximum value may be set as the size of the target position. Alternatively, the size of the speckle grain at the position 202 may be measured, and an area within the measured size may be set as the size of the target position. In this way, the target position of the wavefront optimization process is corrected (corrected) from the initial target position 201 to the newly selected position 202.

  By correcting the target position in this manner, the wavefront optimization process (S1200) can be executed in a state where the initial signal strength is high. The correction of the target position is performed within a range of a minute distance that can be allowed with respect to an arbitrarily set initial target position, and is a correction that does not cause any practical problems as a light irradiation apparatus. Thus, the SNR in the initial state of the wavefront optimization process can be improved by finely correcting the target position within the allowable range.

  In addition, when there are a plurality of speckle grains having a signal intensity equal to or greater than a threshold value in the target vicinity region 210, the target position is corrected to the speckle grain position closer to the initial target position 201. It is preferable. The threshold can be arbitrarily set according to the SNR of the measurement.

  If there is no signal having a signal strength greater than or equal to the threshold in the target vicinity area 210, the threshold may be lowered or the target vicinity area 210 may be expanded within an allowable range to search for a position where a signal above the threshold exists. Good.

  By executing the wavefront optimization process using the target position corrected from the initial target position in this way, a focus spot can be efficiently formed based on the corrected target position. Furthermore, it is possible to evaluate the optical characteristics at the same position by changing the wavelength of the light source 100 and executing the wavefront optimization process and measuring the enhanced signal for each wavelength.

  As described above, in this embodiment, the target position after the correction process is performed after performing the correction process for moving the target position that finally forms the focus spot from the initial target position to a position where higher signal intensity can be obtained. Wavefront optimization processing is executed on Furthermore, in this embodiment, the initial value of the signal strength in the wavefront optimization process is set to be equal to or higher than the average value of the signal strength in the initial state before the execution of the wavefront optimization process.

  FIG. 6 shows the configuration of an imaging apparatus as a light irradiation apparatus that is Embodiment 2 of the present invention. The light source 300 has a wavelength from the visible range to the near infrared range, and emits light that excites the phosphor 321 inside the sample 320. The phosphor may be a fluorescent dye injected into the sample 320 from the outside, or may be an autophosphor resulting from the structure in the sample 320. The sample 320 is a living tissue, and is a scattering medium for incident light 316 from the SLM 303 described later.

  The light emitted from the light source 300 is converted into parallel light having an appropriate beam diameter by the optical system 301, passes through the BS 302, and enters the SLM 303. Incident light 316 phase-modulated by the SLM 303 passes through a dichroic mirror (DM) 305 and forms an image on the surface of the sample 320 at an appropriate magnification by the optical system 304 and the optical system 306. The light incident on the sample 320 reaches the phosphor 321 while being scattered inside the sample 320, and excites the phosphor 321 to generate fluorescence. The fluorescence 318 generated from the phosphor 321 is emitted from the sample 320 while being scattered inside the sample 320, passes through the optical system 306, is reflected by the DM 305, and is imaged as a fluorescent signal by the CCD 309 via the optical system 307. A wavelength filter 308 that allows only the wavelength region of the fluorescence 318 to pass is disposed on the front surface of the CCD 309, whereby the CCD 309 efficiently images only the fluorescence 318. The SLM 303 and the CCD 309 are connected to the PC 310 and are controlled by the PC 310. Also in the present embodiment, similarly to the first embodiment, the wavefront of the incident light 316 incident on the sample 320 is formed by the SLM 303 based on the signal intensity measured (detected) by the CCD 309.

  The flowchart of FIG. 7 shows the flow of processing until an image is generated in this embodiment. First, in S1000, the PC 310 sets an initial target position for forming a focus spot. The initial target position is set in the vicinity of the position where the phosphor exists using some prior information. As prior information, information provided by other modalities such as results measured using X-rays, MRI, ultrasound, light, etc., and other pathological diagnostic results, in addition to the imaging apparatus of the present embodiment. Can be used. In S1000, the PC 310 also sets the target size (target area).

  The PC 310 having set the initial target position in S1000 performs correction processing for correcting the signal obtained at the target position in S1100 as described below.

  FIG. 8 shows a fluorescent image 330 captured by the CCD 309. The fluorescence image 330 includes an intensity distribution of fluorescence (fluorescence signal) 318 generated at a depth at the focal position of the optical system 306 within the sample 320. A position 331 in the figure is the initial target position set in S1000. As described in the first embodiment, attention is focused on a plurality of positions having a signal intensity equal to or higher than a threshold value in the target vicinity region. A position having the maximum signal intensity is extracted from the plurality of positions, and an area within the target size range centered on the position is set as a target signal position (specific position) 332. In the present embodiment, as shown in the first embodiment, the initial target position 331 is not corrected to the target signal position 332, but correction processing for shifting the signal intensity of the target signal position 332 to the initial target position 331 is performed.

  In the plane of the observed fluorescence image 330, the center of the position 331 and the center of the position 332 are separated by ΔX in the X direction and ΔY in the Y direction. At this time, the direction (inclination) of the SLM 303 is adjusted so that the target signal position 332 is shifted by ΔX and ΔY in the X and Y directions, respectively, and overlaps the initial target position 331. For example, the SLM 303 is fixed to the multi-axis stage, and the inclination of the SLM 303 with respect to the sample 320 is adjusted in each of X and direction. From the shift amount ΔX and the distance from the SLM 303 to the observation surface, an angle (tilt angle) for tilting the SLM 303 in the X direction can be obtained. The fluorescence signal at the signal position of interest 332 can be moved to the initial target position 331 by adjusting the shift of ΔX and ΔY with the inclination angle of the SLM 303. Further, the shift may be performed by giving a linear phase shift amount to the phase distribution set in the SLM 303 in each of the X and Y directions according to the inclination angle. In this case, the wavefront optimization process is performed using the phase distribution given the linear shift amount as the initial value of the SLM 303. Furthermore, instead of the SLM 303 or together with the SLM 303, the direction (tilt) of the lens 108 that is an optical system may be changed.

  As described above, the initial signal strength in the wavefront optimization process can be increased by shifting the signal having the signal strength equal to or higher than the threshold value in the vicinity of the initial target position 331 to the initial target position.

  After correcting the signal at the target position as described above in S1100 of FIG. 7, in S1200, the PC 310 forms a focus spot at the target position 331, and the wavefront optimization process described in the first embodiment (FIG. 2). S1200) shown in FIG. When the measurement speed is required, the signal intensity at the target position 331 may be monitored, and the wavefront optimization process may be terminated and the process may proceed to the next step S1300 when the sufficient signal intensity is reached. Further, it is not always necessary to execute the wavefront optimization process for all segments.

  In the next S1300 and subsequent steps, the PC 310 performs imaging using the generated focus spot. FIG. 9 schematically shows imaging in S1300. The PC 310 performs a scan 337 for sequentially moving the focus spot 331 generated at the target position in the horizontal direction with respect to the object plane 336 serving as an imaging region. The scan may be performed in order in the X direction and the Y direction in the object plane 336, or may be performed in a spiral. This scan uses a scattering correlation called the memory effect. By using this memory effect, it is possible to maintain the focus spot without having to perform the wavefront optimization process again using the optimized phase distribution of the SLM 303 already obtained by the wavefront optimization process.

  As described above, the focus spot may be scanned by tilting the SLM 303 fixed to the multi-axis stage in accordance with the scan shift amount, or control a biaxial mirror disposed at a position conjugate with the SLM 303. You may go by. Further, scanning may be performed by adding the linear phase shift amount to the phase distribution of the SLM 303 already obtained in accordance with the shift amount.

  If the angle range θ in which the memory effect is obtained, that is, the effect of the wavefront optimization process is obtained, for example, the intensity range in which the focus peak intensity is 1 / e,

Can be estimated. λ is the wavelength of the incident light 316, and L is the thickness of the medium (the distance from the surface of the sample 320 to the object surface 336). In this embodiment, the PC 310 sets an area to be imaged (generates an image) by the scan within an angle range where the memory effect can be obtained.

  In S1300, the PC 310 measures (detects) the fluorescence signal at each scan position (detection position) while scanning the focus spot 350. The step size (shift amount) at the time of scanning can be arbitrarily set according to the imaging resolution. When the measurement of the fluorescence signal on the object plane 336 is completed, the PC 310 proceeds to S1400.

In S1400, the PC 310 as the image generation unit generates an image by mapping the fluorescence signal corresponding to each measurement position, and displays the obtained image on an image display device such as a display. When the focus spot is scanned, the peak intensity of the focus spot is attenuated according to the shift amount from the position 331 where the focus spot was generated in S1200. This attenuation effect is a correlation function derived from a theoretical model of the memory effect,
C (qL) = [qL / sinh (qL)] ²
The spot intensity attenuation may be corrected by fitting. Furthermore, by arranging the sample 320 on a movable stage and moving the stage in the optical axis direction, images at different depth positions can be imaged.

  Further, in order to widen the imaging area, it is possible to perform the wavefront optimization process again at the boundary position of the range where the memory effect can be obtained to re-form the focus spot, and to continue scanning and imaging.

  By the processing of S1000 to S1400 described above, the signal intensity of the fluorescent signal inside the sample 320 such as a biological tissue can be enhanced, and imaging can be performed with higher accuracy.

  In this embodiment, the initial value of the signal intensity in the wavefront optimization process is sufficiently increased by shifting the signal intensity distribution in the imaging region so that the signal intensity at the initially set target position is equal to or greater than the threshold value. be able to.

  The fluorescence signal referred to in this embodiment includes a signal emitted by multiphoton excitation of a nonlinear phenomenon. Further, in this embodiment, not only imaging using a fluorescence signal but also irradiating the medium with light, and measuring the second harmonic (SHG) and third harmonic (THG) inside the medium. You may apply when imaging. Further, the present embodiment may be applied to imaging of a Raman scattering signal caused by Raman scattering including stimulated Raman scattering (SRS) and coherent anti-Stokes Raman scattering (CARS). In addition, this embodiment may be applied to imaging of optical interference signals in OCT (Optical Coherence Tomography).

  FIG. 10 shows a configuration of an imaging apparatus as a light irradiation apparatus that is Embodiment 3 of the present invention. The imaging apparatus of the present embodiment is a photoacoustic imaging apparatus using light focusing by the wavefront optimization process described in the first embodiment.

  The sample 420 is a living tissue and includes scattering particles 421. The sample 420 is a scattering medium for light from the visible range to the near infrared range. The light source 400 emits pulsed light of several ns. Further, as the wavelength of the light source 400, a plurality of wavelengths can be selected according to absorption spectra of water, fat, protein, oxyhemoglobin, reduced hemoglobin, and the like, which are main components of the living tissue 420. For example, as the light source 400, an electromagnetic wave source that emits a wavelength in a range from the visible range to the near infrared range, such as 400 to 1500 nm, can be used.

  The light emitted from the light source 400 passes through the beam splitter 401 and enters the SLM 402. The SLM 402 is controlled by the control unit (control means) 405 and shapes the wavefront of the light 410 incident on the sample 420 by the wavefront optimization process described above. The light 410 reflected by the SLM 402 and wave-shaped is reflected by the beam splitter 401 and irradiated onto the sample 420 via the optical system 403.

  The light 411 incident on the sample 420 which is a scattering medium propagates inside the sample 420 while being scattered, and a part of the energy is absorbed by the absorber in the local region 425 as a certain position inside the sample 420. As a result, the temperature of the local region 425 increases, the volume of the local region 425 expands, and an acoustic wave (photoacoustic signal) 423 is generated. An ultrasonic device (detection means) 404 including an ultrasonic transducer measures (detects) the photoacoustic signal 423. At this time, the control unit 405 controls the ultrasonic device 404 to control the focus of the ultrasonic transducer so that a signal including the photoacoustic signal 423 from the local region 425 in the sample 420 is detected.

  The ultrasonic transducer is composed of, for example, a linear array probe, and can generate an ultrasonic focus region at an arbitrary position inside the sample 420 by electronic focusing using the array probe. As the transducer, a transducer using a piezoelectric phenomenon, a transducer using optical resonance, a transducer using capacitance change, or the like can be used. The ultrasonic transducer is also acoustically aligned with the sample 420.

The photoacoustic signal P (z) at the position where the depth from the incident position of the light 411 inside the sample 420 is z is expressed by the following equation (1). In formula (1), Φ (z) is the light intensity at the position z, and μ _a (z) is the absorption coefficient of the absorber at the position z. Γ is a Gruneisen coefficient representing the conversion efficiency from heat to acoustic waves.

As can be seen from the equation (1), if the Gruneisen coefficient Γ and the absorption coefficient μ _a (z) are specific to the medium and constant at the position z, the photoacoustic signal changes according to the light intensity at the position z. . Therefore, if the light is efficiently focused on the position z, the signal intensity of the photoacoustic signal P (z) increases.

  The SLM 402 is disposed on the pupil plane of the optical system 403, and each segment on the SLM 402 shapes the wavefront of the incident light 410 independently. A photoacoustic signal generated from the local region 425 is used as a signal to be monitored in the wavefront optimization process. As the wavefront optimization process, the process shown as S1200 in FIG. 2 may be used, or the genetic algorithm described above may be used. In this embodiment, wavefront optimization processing is performed using this photoacoustic signal as a target to increase the signal intensity of the photoacoustic signal as an initial value in the wavefront optimization processing.

  FIG. 11 shows a correction process for the initial value of the signal intensity of the photoacoustic signal in this embodiment. In the correction processing, first, an initial target position (local region) 450 is set at an arbitrary position in an imaging region where photoacoustic imaging is performed inside the sample 420. The initial target position 450 may be set based on prior information such as a diagnostic result acquired in advance or an ultrasonic echo image acquired using the ultrasonic device 404. For example, in an ultrasonic echo image, a region where some signal change is recognized is set as an imaging region for performing photoacoustic imaging, and an initial target position 450 is arbitrarily set within the region imaging region. In addition to the ultrasonic echo image, the initial target position 450 may be set using a photoacoustic signal acquired in advance.

Next, the distribution of photoacoustic signals at positions Z _{0 to} Z _n at different depths in the target vicinity region 460 that is the region near the initial target position 450 inside the sample 420 is used by using the ultrasonic device 404. To obtain three-dimensional data of signal intensity. The target vicinity region 460 is set in a three-dimensional manner within a range in which the correction of the focus spot of incident light can be allowed. Inside the target vicinity region 460, there are a plurality of positions of interest 451 to 453 where the photoacoustic signal is relatively large. Of these attention positions 451 to 453, the attention position (specific position) 453 having the maximum signal intensity is selected. Then, the target position is corrected (corrected) from the initial target position 450 to the target position 453, and wavefront optimization processing is performed using the signal intensity here as an initial value.

  Also in the present embodiment, as described in the second embodiment, it is possible to scan and image the focus spot within the target vicinity region 460 or the range where the memory effect can be obtained. Alternatively, the wavefront optimization process may be performed again at the boundary position of the range where the memory effect can be obtained to re-form the focus spot, and the focus spot may be scanned and imaged.

  The image generated by the photoacoustic imaging in this manner is displayed on the display 406. It is also possible to display this image superimposed on other diagnostic results and measurement data.

  Furthermore, the above-described processing is performed using a plurality of arbitrary wavelengths, the spectral characteristics inside the sample are measured, the component ratio of oxygenated hemoglobin, reduced hemoglobin, water, and the like, and metabolic information such as oxygen saturation are obtained. Can be imaged as a three-dimensional tomographic image.

Further, as a signal to be monitored, a signal indicating the light intensity of the ultrasonic modulated light can be used instead of the photoacoustic signal. As disclosed in Document C below, the ultrasonic-modulated light is light that has been modulated with ultrasonic waves and frequency-shifted by irradiating the sample with light and ultrasonic waves. For example, focused ultrasound that is focused on a position inside the sample is irradiated. Then, at that position, the light whose frequency is shifted according to the frequency of the ultrasonic wave irradiated with the frequency is measured as a monitor signal. At this time, a monitor signal is measured by using a single sensor such as a photodiode (PD), an avalanche photodiode (APD) and a photomultiplier tube (PMT), a lock-in amplifier or a band-pass filter. Are used in combination. Instead of these, a two-dimensional sensor array in which an image intensifier is combined with a CCD sensor, a CMOS sensor, an EMCCD sensor, or a CCD sensor may be used.
(Document C) JP 2010-71692 A

  Next, the structure of the phototherapy apparatus as a light irradiation apparatus which is Example 4 of this invention is shown. The phototherapy apparatus according to the present embodiment is used for photodynamic therapy or the like using the light focusing by the wavefront optimization process described in the first embodiment.

  FIG. 10 is used again to explain the present embodiment. Also in this embodiment, the position where the light focus spot is formed is set as the target position (local region 425). The target position 425 is set to a position where treatment is to be performed based on various diagnosis results performed in advance. A focus pot is formed at the target position 425 by performing wavefront optimization processing using the photoacoustic signal as a monitor signal so that the light is focused on the target position 425. At this time, the photoacoustic signal (initial value) at the target position 425 is corrected so that the wavefront optimization process can be performed with a good SNR.

  In this embodiment, an arbitrary phase pattern is set in the SLM 402, and the photoacoustic signal at the target position 425 is set in the SLM 402 so as to be equal to or higher than a threshold value (predetermined value) as an average signal intensity in a nearby region, for example. Adjust the phase pattern to be applied. The phase pattern applied to the SLM 402 may be a completely random phase pattern or a phase pattern in which orthogonal basis vectors are appropriately added. A plurality of phase patterns are sequentially given to the SLM 402, and wavefront optimization processing is executed when the photoacoustic signal at the target position 425 exceeds a threshold value.

  After the focus spot is formed, the light source 400 may be switched to a light source used for therapeutic purposes. For example, a laser light source having the same wavelength and a larger output is switched. Alternatively, the light source 400 may not be switched, and the sample 402 may be irradiated with light by adjusting the output of the light source 400 to be larger than that during the wavefront optimization process.

As described above, in each of the above embodiments, when appropriately shaping the wavefront of light incident on the medium, correction processing is performed to correct the initial value of the intensity of the signal to be monitored and the position at which the signal intensity is monitored. As a result, the SNR of the signal to be monitored can be improved. As a result, it is possible to form a focus spot with increased light intensity at the monitor position. Then, by combining this wavefront optimization process with various imaging methods and apparatuses, it is possible to perform imaging and treatment more efficiently. (Other examples)
The present invention supplies a program that realizes one or more functions of the above-described embodiments to a system or apparatus via a network or a storage medium, and one or more processors in a computer of the system or apparatus read and execute the program This process can be realized. It can also be realized by a circuit (for example, ASIC) that realizes one or more functions.

  Each embodiment described above is only a representative example, and various modifications and changes can be made to each embodiment in carrying out the present invention.

100 light source 107 spatial light modulator 108 lens 110 imaging device (CCD)
111 Personal computer (PC)
125 samples

Claims (10)

Spatial light modulation means for modulating the light from the light source to shape the wavefront of the light;
An optical system for irradiating a medium with light having the wavefront formed thereon;
Detecting means for detecting a signal generated from the medium irradiated with the light;
Control means for performing optimization processing for shaping the wavefront in the spatial light modulation means so that the intensity of the signal detected at a detection position inside or outside the medium increases,
The control means acquires an intensity distribution of the signal in a predetermined region including the detection position, performs a correction process for correcting the detection position or the signal based on the intensity distribution, and the signal after the correction process The light irradiation apparatus is characterized in that the optimization process is performed so that the intensity of the light increases.   In the correction process, the control means moves the detection position to a specific position where the intensity of the signal before the correction process is performed is equal to or greater than a predetermined value or is maximum in the intensity distribution. The light irradiation apparatus according to claim 1.   The control means detects, in the correction process, a specific position where the intensity of the signal in the intensity distribution is equal to or greater than a predetermined value or the maximum in the intensity distribution, and the specific position moves to the detection position. The light irradiation apparatus according to claim 1, wherein the signal is corrected by controlling the spatial light modulation unit.   The control means detects, in the correction process, a specific position where the intensity of the signal in the intensity distribution is equal to or greater than a predetermined value or the maximum in the intensity distribution, and the specific position moves to the detection position. The light irradiation apparatus according to claim 1, wherein the signal is corrected by changing a direction of at least one of the spatial light modulation unit and the optical system.   The said control means changes the wave front of the said light from the said spatial light modulation means so that the intensity | strength of the said signal in the said detection position may become more than predetermined value in the said correction process. Light irradiation device.   The light irradiation apparatus according to claim 2, wherein the predetermined value is an average signal intensity in the intensity distribution before the correction process is performed or higher. The control means controls the spatial light modulation means so as to sequentially move the detection position within a range where the effect of the optimization process can be obtained,
The light irradiation apparatus according to claim 1, further comprising an image generation unit configured to generate an image using the signals detected at the detection positions that sequentially move.   The signal is any one of light transmitted through the medium, photoacoustic signal, ultrasonic modulated light, fluorescence, second or third harmonic, Raman scattering signal, and optical interference signal. The light irradiation apparatus as described in any one of Claim 1 to 7. Spatial light modulation means for modulating the light from the light source to shape the wavefront of the light, an optical system for irradiating the medium with the light with the wavefront shaped, and a signal generated from the medium irradiated with the light Providing a detecting means;
A control step of performing an optimization process for shaping the wavefront in the spatial light modulator so that the intensity of the signal detected at a detection position inside or outside the medium increases,
In the control step, an intensity distribution of the signal in a predetermined region including the detection position is acquired, a correction process for correcting the detection position or the signal based on the intensity distribution is performed, and the signal after the correction process The light irradiation method is characterized in that the optimization process is performed so that the intensity of light increases. Spatial light modulation means for modulating the light from the light source to shape the wavefront of the light, an optical system for irradiating the medium with the wavefront shaped light, and a signal generated from the medium irradiated with the light A computer program for causing a computer used with the detecting means to perform an optimization process for causing the spatial light modulating means to shape the wavefront so that the intensity of the signal detected at a detection position inside or outside the medium is increased. Because
Obtaining an intensity distribution of the signal in a predetermined region including the detection position;
A correction process for correcting the detection position or the signal based on the intensity distribution;
A light irradiation program characterized by causing the optimization process to be performed so that the intensity of the signal after the correction process is increased.