WO2019074634A1 - Managing activity of brown adipose tissue - Google Patents

Abstract

Examples of the disclosure enable activity of brown adipose tissue to be managed in an efficient, effective, safe, and calculated manner. A method for managing activity of brown adipose tissue includes positioning a subject sensor proximate to the brown adipose tissue, positioning an array device including a plurality of stimulators, activating the plurality of stimulators, receiving a plurality of test temperatures associated with the brown adipose tissue from the subject sensor, and selecting a first stimulator from the plurality of stimulators based on the plurality of test temperatures for managing the activity of the brown adipose tissue.

Description

MANAGING ACTIVITY OF BROWN ADIPOSE TISSUE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent

Application No. 62/571,406, filed on October 12, 2017, the disclosure of which is incorporated by reference herein in its entirety.

BACKGROUND

[0002] Brown adipose tissue may be modulated to induce weight loss and/or treat various conditions. However, known methods and systems for modulating activity of brown adipose tissue involve positioning electrodes at the brown adipose tissue itself for direct stimulation of the brown adipose tissue using electrical impulses.

[0003] In homeothermic animals the central nervous system regulates body temperature (TCORE) within a narrow range that is determined primarily by the neural control of thermoeffector mechanisms. Neurons in the preoptic area (POA) of the hypothalamus are a fundamental component within the hierarchical organization of the neural circuits controlling thermoeffector activity. The discovery of

intrinsically thermosensitive neurons within the POA have led to the concept that TCORE is primarily sensed by such POA neurons and that the discharge of intrinsically thermosensitive neurons in the POA sets the basal tone of the

thermoregulatory system upon which other afferent inputs act, including those from cutaneous thermoreceptors. This idea is supported by the consistent demonstration that the local temperature of the POA can affect thermoeffector output.

[0004] BAT is the principle contributor to non-shivering thermogenesis in response to cold exposure, especially in rodents. Extensive work has defined the neural circuits controlling BAT sympathetic nerve activity (SNA). Since the rediscovery of BAT in adult humans there has been a robust interest in harnessing the activation of BAT for therapeutic purposes. Surprisingly, whether direct cooling of the POA increases sympathetic outflow to BAT is unknown. Accordingly, there exists a need for determining the neuroanatomical pathways that are required for the POA cooling-evoked increase in BAT SNA and BAT thermogenesis. There also exists a need for developing methods and systems for use in therapeutic approaches for POA cooling to treat diseases such as obesity by increasing BAT energy expenditure, and thus its consumption of plasma glucose and fatty acid.

SUMMARY

[0005] Examples of the disclosure enable activity of brown adipose tissue to be managed in an efficient, effective, safe, and calculated manner. A method for managing activity of brown adipose tissue includes positioning a subject sensor proximate to the brown adipose tissue, positioning an array device including a plurality of stimulators proximate to a preoptic area, activating the stimulators, receiving a plurality of test temperatures associated with the brown adipose tissue from the subject sensor, and selecting a first stimulator from the plurality of stimulators based on the test temperatures for managing the activity of the brown adipose tissue.

[0006] In another aspect, a system is provided for managing activity of brown adipose tissue. The system includes a subject component including a sensor that detects a temperature associated with the brown adipose tissue, a target component including a plurality of stimulators that systematically stimulate a preoptic area, and a hub component coupled to the subject component and to the target component. The hub component is configured to monitor the temperature associated with the brown adipose tissue and, based on the monitored temperature, select a first stimulator from the plurality of stimulators for managing the activity of the brown adipose tissue.

[0007] In yet another aspect, an assembly is provided for managing activity of brown adipose tissue. The assembly includes a subject thermistor positionable proximate to the brown adipose tissue, an array device including a plurality of thermodes positionable proximate to a preoptic area and one or more target thermistors proximate to the thermodes, and a control system coupled to the subject thermistor and to the array device. The control system is configured to activate the thermodes, receive a plurality of test temperatures associated with the brown adipose tissue from the subject thermistor, select a first thermode from the plurality of thermodes based on the test temperatures for managing the activity of the brown adipose tissue, and monitor the first thermode using the target thermistors. Each test temperature of the plurality of test temperatures corresponds to a respective thermode set of the plurality of thermodes.

[0008] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 is a block diagram illustrating an example system for managing activity of brown adipose tissue (BAT).

[0010] FIG. 2 is a perspective view of a system for managing BAT activity, such as the system shown in FIG. 1, in an example environment.

[0011] FIG. 3 is a flowchart of an example method for using a system, such as the system shown in FIG. 1, to manage BAT activity.

[0012] FIGS. 4-6 are graphs illustrating example test data for using a system, such as the system shown in FIG. 1, to manage BAT activity.

[0013] FIG. 7 is a block diagram illustrating an example control system for operating a system, such as the system shown in FIG. 1, to manage BAT activity.

[0014] FIG. 8 is a block diagram illustrating an example operating environment in which a control system, such as the control system shown in FIG. 7, may be operated.

[0015] FIG. 9 is a sequence diagram illustrating example operations for managing BAT activity using various subsystems of a system, such as the system shown in FIG. 1.

[0016] FIGS. 10A-10F depict increased brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (TBAT), expired carbon dioxide (Exp C0₂) and heart rate (HR) by decreasing the temperature of the preoptic area (TPOA). FIG. lOA depicts a representative example of the effect of POA cooling (between vertical dashed lines) on the recorded variables. FIG. 10B depicts group data (mean ± SE, n=8). Each time point represents 30 second averages. Statistical comparisons were made between the control pre-cooling level, the cold-evoked level at the 10 minute time point of cooling, and the post-cooling level at 5 minutes after terminating the cooling. * indicates a significant difference from the control pre- cooling level (p<0.05). FIG. IOC depicts a representative example of the effect of prolonged POA cooling. FIG. 10D depicts group data (mean ± SE, n=4). * indicates a significant difference (p<0.05) from the control (ctrl) value, ns, not significant. FIG. 10E depicts a representative photomicrograph of the location of the thermodes (area indicated by the outline and arrows). FIG. 1 OF is a schematic illustrating the location of thermodes (shaded region encompasses the entire area in which thermode tracts were found in all rats). The level of the coronal schematic was approximately at bregma, ac, anterior commissure; AP, arterial pressure; bpm, beats per minutes; ox, optic chiasm.

[0017] FIGS. 11 A-l 1C depict reversal of the increase in brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (TBAT), expired carbon dioxide (Exp. CO2) and heart rate (HR), evoked by decreasing the preoptic area temperature (TPOA) by nanoinjection of AP5/CNQX into raphe pallidus (RPa). FIG. 11 A depicts a representative example of the effect of AP5/CNQX injection into RPa (vertical dashed line) on the recorded parameters, during local POA cooling. FIG. 1 IB depicts group data (mean ± SE, n=5) for the time course of the responses to AP5/CNQX (filled triangle) or saline vehicle injection into RPa (empty circle), during POA cooling. Each time point represents 30 second averages. * indicates a significant difference (p<0.05) between the value at the fifth minute of cooling versus the control pre-cooling value, for both the AP5/CNQX trial and the vehicle trial. # indicates a significant difference (p<0.05) between the AP5/CNQX-induced change from the cooling-induced peak versus the change from the cooling-induced peak following vehicle, ns, not significant. FIG. 11C depicts (i) a photomicrograph of a representative nanoinjection site in the RPa (beads indicated by the arrow); and (ii) the locations of the nanoinjection sites represented by squares (n=5) plotted on a schematic drawing of a partial coronal section at approximately -11.8mm caudal to bregma.

[0018] FIGS. 12A-12C depict reversal of the increase in brown adipose tissue sympathetic nerve activity (BAT SNA), BAT temperature (TBAT), expired carbon dioxide (Exp. C0₂), and heart rate (HR), evoked by decreasing the preoptic area temperature (TPOA) by bilateral nanoinjections of AP5/CNQX into dorsomedial hypothalamus (DMH). FIG. 12A is a representative example of the effect of

AP5/CNQX injections into DMH (indicated by two vertical dashed lines; bilateral injections: R, right side and L, left side) on the recorded parameters during POA cooling. FIG. 12B depicts group data (mean ± SE, n=5) for the time course of the responses to AP5/CNQX (filled triangles) or saline vehicle injections (empty circle) into DMH, during POA cooling. Each time point represents 30 second averages. * indicates a significant difference (p<0.05) between the value at the fifth minute of cooling versus the control pre-cooling value, for both the AP5/CNQX trial and the vehicle trial. # indicates a significant difference (p<0.05) between the AP5/CNQX induced change from the cooling-induced peak versus the change from the cooling- induced peak following vehicle, ns, not significant. FIG. 12C depicts (i) a

photomicrograph of a representative nanoinjection site in the DMH (arrow indicates blue bead deposits), and (ii) a schematic plot of the injection sites in the DMH (blue circles) on a coronal section at—3.0 mm to -3.3 mm caudal to bregma.

[0019] FIGS. 13A-13E depict reversal of the increase in brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (TBAT), expired carbon dioxide (Exp CO2) and heart rate (HR) evoked by decreasing preoptic area temperature (TPOA) by nanoinjection of either muscimol or AP5/CNQX in median preoptic nucleus (MnPO). Representative examples of the effect of muscimol injection (FIG. 13 A, vertical dashed line) or AP5/CNQX injection (FIG. 13B, vertical dashed line) into MnPO on the recorded variables, during POA cooling. FIG. 13C depicts group data (mean ± SE, n=5) for the time course of the responses to muscimol (filled squares), AP5/CNQX (filled triangles) and saline vehicle (empty circles) injections into MnPO, during POA cooling. Each time point represents 30 second averages. * indicates a significant difference (p<0.05) between the value at the fifth minute of cooling versus the control pre-cooling value, for each group. # indicates a significant difference (p<0.05) between the muscimol-induced and AP5/CNQX- induced changes from the cooling-induced peak compared to the vehicle-induced change from the cooling-induced peak, ns, not significant. Photomicrographs (i) and schematic representations (ii) of the nanoinjection sites in MnPO, arrows (i) and squares (ii) indicate the locations of bead deposits for muscimol (FIG. 13D) and AP5/CNQX (FIG. 13E). Schematic representations are plotted on a partial coronal section at ~ 0.0 mm to +0.2 mm rostral to bregma.

[0020] Corresponding reference characters indicate corresponding parts throughout the drawings.

DETAILED DESCRIPTION

[0021] The subject matter described herein relates generally to medical devices and, more specifically, to methods and systems for managing activity of brown adipose tissue (BAT). Examples of the disclosure may be used, for example, to deep brain cool a preoptic area (POA) of a hypothalamus to stimulate BAT activity. Stimulating BAT activity may induce weight loss and/or treat one or more conditions, such as obesity, a metabolic disorder, diabetes, betabolic syndrome, dyslipidemia, and/or hypercholesterolemia.

[0022] Examples described herein include a thermistor proximate to the BAT, a plurality of thermodes proximate to the POA, and a control system configured to select, from the plurality of thermodes, a first thermode for managing activity of the BAT in an effective and efficient manner. The thermodes may be systematically tested or evaluated to identify a thermode (e.g., a first thermode) that is effective and/or efficient relative to a predetermined standard and/or relative to the other thermodes. Additionally, the thermistor, thermodes, and/or their respective environments may be monitored to mitigate risk and/or ensure that the thermistor and/or thermodes are utilized in a safe and calculated manner.

[0023] The systems and processes described herein may be implemented using computer programming or engineering techniques including computer software, firmware, hardware, or a combination or subset thereof. While the examples described herein are described in regard to deep brain cooling a POA for managing activity of BAT, it should be understood that the examples described herein may be used to systematically activate any stimulator(s) and/or actuator(s) to identify a stimulator and/or actuator that is effective, efficient, and safe without departing from the present disclosure.

[0024] The technical effect of the systems and processes described herein is achieved by performing at least one of the following operations: a) activating one or more stimulators; b) receiving one or more temperatures associated with a subject and/or target of the stimulators; c) comparing the temperatures with one or more other temperatures; d) determining whether the temperatures satisfy one or more predetermined thresholds; e) generating one or more alerts; f) waiting one or more predetermined periods of wait time; and/or g) selecting one or more stimulators for managing an activity of the BAT.

[0025] FIG. 1 shows an example assembly or system 100 including one or more subject sensors 110 and an array device 120. The subject sensors 110 are implantable in or positionable at a body proximate to a subject of the body such that the subject sensors 110 are configured to sense or detect the subject and/or an activity of the subject. In this manner, the subject sensors 110 may be used to monitor the subject. In some examples, a subject sensor 110 is or includes a thermometer, a thermistor, a thermocouple, and/or a resistive temperature detector that senses or detects a temperature. Alternatively, the subject sensor 110 may be configured to sense or detect any parameter that enables the subject to be monitored, such as a hydrogen ion concentration (pH), a partial pressure of carbon dioxide (pC0₂), blood flow, blood pressure, blood oxygenation, heart rate, an electrical activity, and the like. [0026] The array device 120 includes a plurality of actuators or stimulators 130 that are implantable in or positionable at the body proximate to a target of the stimulators 130 such that the stimulators 130 are configured to stimulate or increase activity of the target. In some examples, a stimulator 130 is or includes an electrode and/or thermode that transmits or delivers a cold stimulus. Alternatively, the stimulator 130 may transmit or deliver any stimulus that enables the system 100 to stimulate or increase activity of the target, such as an electrical impulse.

[0027] The array device 120 may include a plurality of target sensors 140. One or more target sensors 140 may be located or positioned proximate to one or more stimulators 130 such that the target sensors 140 are configured to sense or detect the stimulators 130, their target, and/or an activity of the stimulators 130 and/or their target. In this manner, the target sensors 140 may be used to monitor the stimulators 130 and/or their target. In some examples, a target sensor 140 is or includes a thermometer, a thermistor, a thermocouple, and/or a resistive temperature detector that senses or detects a temperature. Alternatively, the target sensor 140 may be configured to sense or detect any parameter that enables a stimulator 130 and/or its target to be monitored, such as a hydrogen ion concentration (pH), a partial pressure of carbon dioxide (pC02), blood flow, blood pressure, blood oxygenation, heart rate, an electrical activity, and the like.

[0028] In some examples, the array device 120 may include one or more components that are configurable between a stimulator mode and a sensor mode. That is, the system 100 may include one or more components that function as a stimulator 130 and as a target sensor 140. In some examples, a controller or control system 150 may be used to selectively switch the components between the stimulator mode and the sensor mode. The controller or control system 150 is coupled to the subject sensors 110 and to the array device 120 for use in operating the system 100. In some examples, the control system 150 is implantable in or positionable at the body.

Alternatively, the control system 150 may be external to or remote from the body.

[0029] The control system 150 is configured to transmit data to and/or receive data from the subject sensors 110, stimulators 130, and/or target sensors 140. Data may be transmitted and/or received, for example, via one or more wired connections and/or using one or more wireless technologies (e.g., radio frequency, BLUETOOTH® wireless communication, ANT+® wireless communication, WI-FI® network communication, ZIGBEE® network communication). (BLUETOOTH® is a registered trademark of Bluetooth Special Interest Group, ANT+® is a registered trademark of Garmin Switzerland GmbH, WI-FI® is a registered trademark of the Wi-Fi Alliance, and ZIGBEE® is a registered trademark of ZigBee Alliance

Corporation).

[0030] The control system 150 is configured to communicate with the subject sensors 110, stimulators 130, and/or target sensors 140. In this manner, the control system 150 may provide instructions to and/or obtain feedback from the subject sensors 110, stimulators 130, and/or target sensors 140. The control system 150 may be used, for example, to systematically position and/or utilize the subject sensors 110, stimulators 130, and/or target sensors 140. Information provided to and/or obtained from the subject sensors 110, stimulators 130, and/or target sensors 140 may be used and/or analyzed to determine whether the stimulators 130 are effective, efficient, and/or safe to activate. In some examples, the control system 150 transmits one or more instructions to the stimulators 130 for activating the stimulators 130 and receives one or more temperatures from the subject sensors 110 and/or target sensor 140 for monitoring subject, stimulator, and/or target activity.

[0031] FIG. 2 shows the system 100 in an example body environment 200. As shown at FIG. 2, the subject sensor 110 may be positioned at or proximate to brown adipose tissue (BAT) 210 such that the subject sensor 110 is configured to sense or detect the BAT 210 and/or its activity. Alternatively, the subject sensor 110 may be positioned at or proximate to any subject that enables the system 100 to function as described herein. In some examples, the subject sensor 110 is positioned and configured to detect a temperature indicative of a thermogenic activity of the BAT 210. The subject sensor 110 may be or include, for example, a thermometer, a thermistor, a thermocouple, and/or a resistive temperature detector positioned proximate to the BAT 210. [0032] As shown at FIG. 2, the array device 120 may be positioned at or proximate to a target region 220 of a brain such that the stimulators 130 are configured to stimulate or increase activity of the target region 220 and the target sensors 140 are configured to sense or detect the stimulators 130, the target region 220, and/or their respective activities. In some examples, the target sensors 140 include a first target sensor 230 positioned to detect a core temperature associated with the target region 220 and a plurality of second target sensors 240 positioned to detect a temperature associated with the stimulators 130. The temperature detected by the second target sensors 240 may be indicative, for example, of an activity of the stimulators 130 and/or the target region 220. In some examples, each second target sensor 240 is proximate to and/or associated with a respective stimulator 130.

Alternatively, the array device 120, stimulators 130, and/or target sensors 140 may be positioned in any combination of locations that enables the system 100 to function as described herein.

[0033] In some examples, the stimulators 130 are positioned and configured to perform deep brain stimulation at a preoptic area (POA) of the hypothalamus for managing activity of the BAT 210. Each stimulator 130 may perform deep brain cooling of the POA by transmitting or delivering a respective cold stimulus to one or more temperature-sensitive cells in the POA to cause a temperature change at the temperature-sensitive cells. Stimulating the POA facilitates increasing thermogenic activity of the BAT 210, which may lead to increased weight loss and/or treatment of various conditions, such as obesity, a metabolic disorder, diabetes, betabolic syndrome, dyslipidemia, and/or hypercholesterolemia.

[0034] The control system 150 is communicatively coupled to the subject sensors 110, stimulators 130, and/or target sensors 140 to enable effective, efficient, and/or safe operation of the subject sensors 110, stimulators 130, and/or target sensors 140. As shown at FIG. 2, the control system 150 may be positioned at or proximate to the BAT 210. Alternatively, the control system 150 may be positioned in any location that enables the system 100 to function as described herein.

[0035] FIG. 3 is a flowchart of an example method 300 for using the system 100 to manage activity of the BAT 210 in the body environment 200. The subject sensor 110 is positioned at operation 310 such that the subject sensor 110 is proximate to the BAT 210. The subject sensor 110 may be positioned proximate to the BAT 210, for example, to monitor activity of the BAT 210.

[0036] The array device 120 is positioned at operation 320 such that the array device 120 is proximate to a preoptic area (POA) of the hypothalamus. The array device 120 may be positioned proximate to the POA, for example, to enable the stimulators 130 to transmit or deliver one or more stimuli to one or more cells in the POA.

[0037] The stimulators 130 are activated at operation 330 to increase activity of the target region 220. Stimuli transmitted or delivered to the cells in the POA, for example, may decrease a temperature of one or more cells proximate to the stimulators 130. In some examples, the stimulators 130 are activated to test a functionality of the stimulators 130 themselves (a "target test"). To perform the target test, a temperature of the target (e.g., cells proximate to the stimulators 130) may be monitored around the time the stimulators 130 are activated. The second target sensors 240, for example, may be used to detect a plurality of temperatures associated with the stimulators 130, including a first temperature and a second temperature for each stimulator 130. The first temperatures may be detected prior to activating the stimulators 130, and the second temperatures may be detected during or within a predetermined time frame of the stimulators 130 being activated.

[0038] To ensure the stimulators 130 have an opportunity to change a activity and/or a parameter (e.g., temperature) of the cells proximate to the stimulators 130, the stimulators 130 may be activated for a predetermined period of activation time. In some examples, the stimulators 130 are systematically activated and/or deactivated such that an effect of each stimulator 130 (e.g., temperature change in the cells proximate to the stimulators 130) may be accurately attributed. The stimulators 130 may be sequentially activated, for example, in one or more stimulator sets (e.g., sets of one stimulator 130) such that a parameter (e.g., temperature) detected by one or more target sensors 140 during or within a predetermined time frame of a particular stimulator set being activated may be associated with that stimulator set. Additionally, each stimulator set may be activated after a predetermined period of wait time since activation or deactivation of the preceding stimulator set.

[0039] The second parameters may be compared with the first parameters to determine whether the stimulators 130 are functional. For example, if a second temperature associated with a stimulator 130 is less than a first temperature associated with the stimulator 130, it may be determined that the stimulator 130 caused the decrease in temperature and, thus, is functional. On the other hand, if the second temperature is greater than or equal to the first temperature, it may be determined that the stimulator 130 is nonfunctional or malfunctioning. Stimulators 130 determined to be nonfunctional or malfunctioning may enter an inactive state, in which the stimulators 130 are restricted from being activated. Stimulators 130 may leave the inactive state (or enter an active state in which the stimulators 130 are allowed to be activated) with user intervention, after a predetermined period of wait time (e.g., expiration of a "lock-out" period), and/or when a stimulator 130 is moved (e.g., repositioned within or removed from the target region 220). If a predetermined number of stimulators 130 are in the inactive state, an alert may be generated and presented to a user of the system 100, and the array device 120 may be repositioned and/or the stimulators 130 may be re-activated.

[0040] In some examples, a core temperature associated with the POA is received from the first target sensor 230, and the second temperatures may be compared with the core temperature to determine whether the stimulators 130 are functional. If a second temperature associated with a stimulator 130 is less than the core temperature, it may be determined that the stimulator 130 caused the decrease in temperature and, thus, is functional. On the other hand, if the second temperature is greater than or equal to the core temperature, it may be determined that the stimulator 130 is nonfunctional or malfunctioning.

[0041] The core temperature may be used to indicate a state of the target region 220 and/or the body environment 200. It may be determined, for example, whether the core temperature satisfies a predetermined core temperature threshold (e.g., is it safe to activate the stimulators 130?). If the predetermined core temperature threshold is not satisfied, an alert may be generated and presented to a user of the system 100, and the target region 220 and/or body environment 200 may be flagged for review. When the target region 220 and/or body environment 200 are flagged for review, the stimulators 130 may enter the inactive state.

[0042] In some examples, the stimulators 130 are activated to test a response of the BAT 210 to the stimulation at the target region 220 (a "subject test"), and a plurality of test temperatures associated with the BAT 210 are received at operation 340 from the subject sensor 110. To perform the subject test, a temperature of the subject (e.g., BAT 210) may be monitored around the time the stimulators 130 are activated. The subject sensor 110, for example, may be used to detect a plurality of test temperatures associated with the BAT 210 during or within a predetermined time frame of the stimulators 130 being activated. Each test temperature may correspond, for example, to a respective stimulator set (e.g., a set of one stimulator 130).

[0043] To ensure the stimulators 130 have an opportunity to stimulate BAT activity, the stimulators 130 may be activated for a predetermined period of activation time. In some examples, the stimulators 130 are systematically activated and/or deactivated such that an effect of each stimulator 130 (e.g., BAT activity) may be accurately attributed. The stimulators 130 may be sequentially activated, for example, in one or more stimulator sets (e.g., sets of one stimulator 130) such that a

temperature detected by one or more target sensors 140 during or within a

predetermined time frame of a particular stimulator set being activated may be associated with that stimulator set. Additionally, each stimulator set may be activated after a predetermined period of wait time since activation or deactivation of the preceding stimulator set.

[0044] The test temperatures may be used to identify and select at operation 350 a stimulator set (e.g., a first stimulator) from the stimulators 130 for managing the activity of the BAT 210. A first test temperature corresponding to the first stimulator may be indicative of more BAT activity than those indicated by the test temperatures corresponding to other stimulators 130. The test temperatures may be compared, for example, with each other, and the highest test temperature (e.g., the first test temperature) may be used to identify the first stimulator for managing the activity of the BAT 210. Additionally or alternatively, the test temperatures may be compared with a baseline temperature to determine which test temperature has the greatest difference from the baseline temperature (as compared to other test temperatures), and that test temperature (e.g., the first test temperature) may be used to identify the first stimulator for managing the activity of the BAT 210. The baseline temperature may be detected by the subject sensor 110, for example, prior to activating the stimulators 130.

[0045] In some examples, it is determined whether one or more monitored temperatures associated with the BAT 210 satisfy a predetermined monitored temperature threshold (e.g., is the BAT temperature within a desired range?). The monitored temperatures may be detected by the subject sensor 110, for example, during or within a predetermined time frame of the first stimulator being activated. If the predetermined monitored temperature threshold is not satisfied, an alert may be generated and presented to a user of the system 100, and the array device 120 may be repositioned and/or the stimulators 130 may be re-activated until the predetermined monitored temperature threshold is satisfied. For example, a second stimulator may be selected from the stimulators 130 for managing the activity of the BAT 210.

[0046] FIGS. 4-6 show example test data 360 for using the system 100 to manage BAT activity. Test data 360 includes plots of data for brain temperature (Tbrain, °C), integrated BAT sympathetic nerve activity (power/4s), actual BAT sympathetic nerve activity (μν), BAT temperature (TBAT, °C), core temperature (TCORE, °C), expired C0₂ (%), skin temperature (T_Skin, °C), heart rate (HR, beats per minute), and arterial blood pressure (AP, mmHg). As shown in FIGS. 4-6, activation of thermogenesis is proportional to the degree of cooling in the POA of the brain, which is determined by the amount of current delivered to the peltier device.

[0047] The test data 360 was collected from tests conducted on male SPRAGUE DAWLEY® brand laboratory rats (SPRAGUE DAWLEY® is a registered trademark of Envigo Holding I, Inc.). The rats were kept on a 12: 12 hour light-dark cycle and given ad libitum access to standard rat chow and water in a colony room maintained at 22-23 °C. The rats were anesthetized with isoflurane (2- 3% in oxygen), instrumented with femoral arterial and venous catheters, and transitioned to urethane and chloralose anesthesia (750 milligrams (mg)/kilogram (kg) and 60 mg/kg, respectively) over a ten minute period. Quantities of anesthesia were determined by identifying an absence of a withdrawal reflex or pressor response to foot pinch and by identifying an absence of a corneal reflex. Physiological variables were digitized using a data acquisition unit and recorded onto a computer hard drive for subsequent analysis.

[0048] Arterial blood pressure was recorded from the arterial catheter attached to a pressure transducer, and heart rate (HR) was derived from the arterial pressure signal. The trachea was cannulated, and the animal was ventilated (tidal volume approximately 1 milliliters (ml)/100 grams (g) body weight at approximately 60 cycles per minute with 100% oxygen. A capnometer was used to measure end- expiratory carbon dioxide (C0₂) via a needle probe inserted into the trachea tube. Colonic (core) temperature (T_COre) was monitored using a copper-constantan thermocouple inserted 6.0 centimeters (cm) into the rectum and maintained between 35-38 °C with a water perfused heating/cooling blanket and a heat lamp.

[0049] The trunk skin was shaved and copper-constantan thermocouples were taped to the hindquarter skin to monitor skin temperature (T_Skin) beneath the heating/cooling blanket and to the forepaw to monitor paw skin temperature (T_paw). The temperature of brown adipose tissue (TBAT) was monitored using a thermocouple meter with a Type T needle-style microprobe thermocouple inserted into the intact, left interscapular BAT fat pad.

[0050] Postganglionic BAT sympathetic nerve activity (SNA) was recorded under mineral oil with a bipolar hook electrode from the central cut end of a small diameter nerve bundle isolated from the ventral surface of the right interscapular fat pad after dividing it along the midline and reflecting it laterally. Nerve activity was filtered (1-300 hertz (Hz)) and amplified (10,000 times) with a programmable signal conditioner. A continuous measure (4 second (s) bins) of BAT SNA amplitude was obtained by calculating the root mean square (rms) amplitude of the BAT SNA (e.g., square root of the total power in the 0.1 to 20 Hz band) from the autospectra of sequential 4 s segments of BAT SNA. Rats were placed in a stereotaxic frame and peltier driven silver thermodes, and a microprobe thermocouple was placed into the preoptic area (POA) to cool this brain region and measure changes in the temperature of the brain (Tbrain) near the cooling thermodes.

[0051] As shown in FIG. 4, thermogenesis may be repeatedly activated in rat BAT by cooling of the POA of the brain. At time 0 indicated at cursor 362, 0.1 amperes (A) of current was delivered to the peltier device, resulting in a rapid decrease in T rain near the POA. This resulted in an increase in BAT SNA and BAT thermogenesis. Thermogenesis is an energy consuming process (as indicated in this example by the increase in expired C0₂) that is the basis for the potential of DBC to cause weight loss. After five minutes, as indicated at cursor 364, the current delivered to the peltier device was terminated, resulting in a rapid return of T rain to levels similar to those prior to cooling, thus terminating the increases in BAT SNA, BAT thermogenesis, and expired CO2. From cursor 366 to cursor 368, current (0.1 A) was continuously delivered to the peltier device, again resulting in a rapid decrease in Tbrain near the POA and driving BAT SNA, BAT thermogenesis, and increasing expired CO2. The decrease in Tbrain and the resulting increases in BAT SNA, TBAT, and expired C0₂were sustained for approximately 15 minutes with continuous delivery of 0.1 mA current to the peltier device. Between cursor 370 and cursor 372, current (0.025 A) was delivered to the peltier device. Such data may be used to select an amount of current that yields desired stimulation parameters for desired BAT temperature increases during DBC.

[0052] As shown in FIG. 5, POA cooling may be sustained to increase BAT SNA and thermogenesis. For approximately 85 minutes, current (0.1 A) was delivered to the peltier device, decreasing Tbrain near the POA by approximately 4.0 °C. The decrease in Tbrain near the POA increased BAT SNA and BAT thermogenesis for the duration of the cooling. When the current to the peltier device was terminated, Tbrain rapidly increased and the increase in BAT SNA and TBAT was rapidly terminated. [0053] FIG. 6 includes plots of group data (n=5) for changes evoked by passing 0.1 A of current to a peltier driven thermode placed in the POA of the brain in rats. Values are mean plus a standard error of the mean.

[0054] FIG. 7 shows an example control system 400 (e.g., control system 150) that may be used to operate the system 100 to manage BAT activity in the body environment 200. The control system 400 may be configured, for example, to activate one or more stimulators 130, receive one or more temperatures (e.g., from subject sensors 110 and/or target sensors 140), and select a first stimulator 130 for managing the activity of the BAT 210. The control system 400 includes an interface component 410, a subject component 420, a target component 430, and a hub component 440.

[0055] The interface component 410 facilitates communication between and among software components, computer hardware, peripheral devices, and/or users. The interface component 410 may allow, for example, the subject component 420, target component 430, and/or hub component 440 to exchange information with each other. In some examples, the interface component 410 enables the control system 150 to receive data from and/or present data to a user. The interface component 410 may communicate, for example, with a user interface that allows the user to enter one or more commands and/or provide information (e.g., user input) to the control system 150. In this manner, the interface component 410 may facilitate communication between the user and the subject component 420, target component 430, and/or hub component 440.

[0056] The subject component 420 controls one or more operations associated with the subject (e.g., BAT 210). The subject component 420 includes a sensor (e.g., subject sensor 110) that detects a temperature associated with the BAT 210 (e.g., test temperature, baseline temperature, monitored temperature).

[0057] The target component 430 controls one or more operations associated with the target (e.g., target area 220). The target component 430 includes a plurality of stimulators (e.g., stimulators 130) that systematically stimulate a preoptic area (POA) of the brain. In some examples, the target component 430 is configured to sequentially activate the stimulators 130. The target component 430 may wait a predetermined period of wait time between activating sequential stimulators 130 (e.g., a first stimulator and a second stimulator). Additionally or alternatively, each stimulator 130 may be activated for one or more predetermined periods of activation time. In some examples, the target component 430 is configured to determine whether a core temperature associated with the POA satisfies a predetermined core

temperature threshold. On condition that the predetermined core temperature threshold is satisfied, the target component 430 may activate one or more stimulators 130 for one or more predetermined periods of activation time. On the other hand, on condition that the predetermined core temperature threshold is not satisfied, the target component 430 may generate an alert and/or wait a predetermined period of wait time (e.g., until the predetermined core temperature threshold is satisfied).

[0058] The hub component 440 is coupled to the subject component 420 and to the target component 430. The hub component 440 is configured to monitor the temperature associated with the BAT 210 and, based on the monitored temperature, select a first stimulator for managing the activity of the BAT 210. The hub component 440 may identify a first test temperature corresponding to the first stimulator (e.g., via the subject component 420), for example, within a predetermined time frame of the first stimulator being activated. Each test temperature may correspond, for example, to a respective stimulator set of the plurality of stimulators 130. In some examples, the hub component 440 is configured to identify a baseline temperature associated with the BAT 210 (e.g., via the subject component 420), identify a plurality of test temperatures associated with the BAT 210 (e.g., via the subject component 420), and compare the test temperatures with the baseline temperature for selecting the first stimulator.

[0059] In some examples, the hub component 440 is configured to identify a plurality of first temperatures associated with the stimulators 130 (e.g., via the target component 430), identify a plurality of second temperatures associated with the stimulators 130 (e.g., via the target component 430), and compare the second temperatures with the first temperatures to determine whether the second temperatures satisfy a predetermined temperature threshold (e.g., a predetermined test temperature threshold, a predetermined monitored temperature threshold). Additionally or alternatively, the hub component 440 may be configured to identify a core

temperature associated with the POA (e.g., via the target component 430), and compare the first temperatures and/or second temperatures with the core temperature to determine whether the first temperatures and/or second temperatures satisfy the predetermined temperature threshold. On condition that the predetermined temperature threshold is satisfied, the target component 430 may activate one or more stimulators 130 for one or more predetermined periods of activation time. On the other hand, on condition that the predetermined temperature threshold is not satisfied, the hub component 440 may configured to generate an alert and/or wait a

predetermined period of wait time (e.g., until the predetermined temperature threshold is satisfied).

[0060] FIG. 8 shows an example operating environment 500 that may be used to enable the system 100 to perform one or more operations. The operating environment 500 is only one example of a computing and networking environment and is not intended to suggest any limitation as to the scope of use or functionality of the disclosure. The operating environment 500 should not be interpreted as having any dependency or requirement relating to any one or combination of components illustrated in the example operating environment 500.

[0061] The disclosure is operational with numerous other computing and networking environments or configurations. While some examples of the disclosure are illustrated and described herein with reference to the operating environment 500 being or including a control system 150 (shown in FIG. 1) or control system 400 (shown in FIG. 7), aspects of the disclosure are operable with any computing system that executes instructions to implement the operations and functionality associated with the operating environment 500.

[0062] For example, the operating environment 500 may include a mobile device, a tablet, a laptop computer, a desktop computer, a server computer, a microprocessor-based system, a multiprocessor system, a communication devices in a wearable or accessory form factor (e.g., a watch, glasses, a headset, earphones, and the like), programmable consumer electronics, a portable media player, a gaming console, a set top box, a kiosk, a tabletop device, an industrial control device, a minicomputer, a mainframe computer, a network computer, a distributed computing environment that includes any of the above systems or devices, and the like. The operating environment 500 may represent a group of processing units or other computing systems. Additionally, any computing system described herein may be configured to perform any operation described herein including one or more operations described herein as being performed by another computing system.

[0063] With reference to FIG. 8, an example system for implementing various aspects of the disclosure may include a general purpose computing system in the form of a computer 510. Components of the computer 510 may include, but are not limited to, a processing unit 520 (e.g., a processor), a system memory 525 (e.g., a computer-readable storage device), and a system bus 530 that couples various system components including the system memory 525 to the processing unit 520. The system bus 530 may be any of several types of bus structures including a memory bus or memory controller, a peripheral bus, and a local bus using any of a variety of bus architectures. By way of example, and not limitation, such architectures include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronics Standards Association (VESA) local bus, and Peripheral Component Interconnect (PCI) bus also known as Mezzanine bus.

[0064] The system memory 525 includes any quantity of media associated with or accessible by the processing unit 520. For example, the system memory 525 may include computer storage media in the form of volatile and/or nonvolatile memory, such as read only memory (ROM) 531 and random access memory (RAM) 532. The ROM 531 may store a basic input/output system (BIOS) 533 that facilitates transferring information between elements within computer 510, such as during startup. The RAM 532 may contain data and/or program modules that are immediately accessible to and/or presently being operated on by processing unit 520. For example, the system memory 525 may store computer-executable instructions, application data, identifier data, profile data, usage data, biometric data, location data, and other data. By way of example, and not limitation, FIG. 8 illustrates operating system 534, application programs 535, other program modules 536, and program data 537.

[0065] The computer 510 includes a variety of computer-readable media. Computer-readable media may be any available media that may be accessed by the computer 510 and includes both volatile and nonvolatile media, and removable and non-removable media. By way of example, and not limitation, computer-readable media may comprise computer storage media and communication media. Computer storage media are tangible and mutually exclusive to communication media.

[0066] Computer storage media includes volatile and nonvolatile, removable and non-removable media implemented in any method or technology, such as semiconductor, magnetic, or optical technologies, for storage of information, such as computer-executable instructions, data structures, program modules or other data. Example computer storage media includes, but is not limited to, ROM 531, RAM 532, electrically erasable programmable read-only memory (EEPROM), solid-state memory, flash memory, a hard disk, magnetic storage, floppy disk, magnetic tape, a compact disc (CD), a digital versatile disc (DVD), a BLU-RAY DISC® brand optical disc, an ultra density optical (UDO) disc, or any other medium which may be used to store the desired information and which may be accessed by the computer 510. (BLU- RAY DISC® is a registered trademark of Blu-ray Disc Association). Computer storage media are implemented in hardware and exclude carrier waves and propagated signals. Computer storage media for purposes of this disclosure are not signals per se.

[0067] Communication media typically embodies computer-executable instructions, data structures, program modules or other data in a modulated data signal such as a carrier wave or other transport mechanism and includes any information delivery media. The term "modulated data signal" means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media includes wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, radio frequency, infrared and other wireless media.

[0068] By way of example only, FIG. 8 illustrates a hard disk drive 541 that reads from or writes to non-removable, nonvolatile magnetic media, a universal serial bus (USB) port 542 that reads from or writes to a removable, nonvolatile memory 543, and an optical disk drive 544 that reads from or writes to a removable, nonvolatile optical disk 545. Other removable/non-removable, volatile/nonvolatile computer storage media that may be used in the example operating environment include, but are not limited to, solid state memory, flash memory, and the like. The hard disk drive 541 may be connected to the system bus 530 through a non-removable memory interface such as interface 546, and magnetic disk drive 542 and optical disk drive 544 may be connected to the system bus 530 by a removable memory interface, such as interface 547.

[0069] The drives and their associated computer storage media, described above and illustrated in FIG. 8, provide storage of computer-executable instructions, data structures, program modules, components (e.g., interface component 410, subject component 420, target component 430, hub component 440), applications, and other data for the computer 510. In FIG. 8, for example, hard disk drive 541 is illustrated as storing operating system 554, application programs 555, other program modules 556 and program data 557. Note that these components may either be the same as or different from operating system 534, application programs 535, other program modules 536, and program data 537. Operating system 554, application programs 555, other program modules 556, and program data 557 are given different numbers herein to illustrate that, at a minimum, they are different copies.

[0070] The processing unit 520 includes any quantity of processing units, and the instructions may be performed by the processing unit 520 or by multiple processors within the operating environment 500 or performed by a processor external to the operating environment 500. The processing unit 520 may be programmed to execute the computer-executable instructions for implementing aspects of the disclosure, such as those illustrated in the figures (e.g., FIGS. 3 and 9). For example, the processing unit 520 may execute an interface component 410 (shown in FIG. 7), a subject component 420 (shown in FIG. 7), a target component 430 (shown in FIG. 7), and/or a hub component 440 (shown in FIG. 7) for implementing aspects of the disclosure. [0071] Upon programming or execution of these components, the operating environment 500 and/or processing unit 520 is transformed into a special purpose microprocessor or machine. For example, the target component 430, when executed by the processing unit 520, causes the computer 510 to activate and monitor the plurality of stimulators 130; the subject component 420, when executed by the processing unit 520, causes the computer 510 to receive a plurality of test

temperatures associated with the BAT 210; and the hub component 440, when executed by the processing unit 520, causes the computer 510 to select a first stimulator based on the test temperatures for managing the activity of the BAT 210. Although the processing unit 520 is shown separate from the system memory 525, examples of the disclosure contemplate that the system memory 525 may be onboard the processing unit 520 such as in some embedded systems.

[0072] A user may enter commands and information into the computer 510 through one or more input devices, such as a pointing device 561 (e.g., mouse, trackball, touch pad), a keyboard 562, a microphone 563, and/or an electronic digitizer 564 (e.g., on a touchscreen). Other input devices not shown in FIG. 5 may include a joystick, a game pad, a controller, a camera, a scanner, an accelerometer, a satellite dish, or the like. The computer 510 may accept input from the user in any way, including from input devices, via gesture input, via proximity input (such as by hovering), and/or via voice input. These and other input devices may be coupled to the processing unit 520 through a user input interface 565 that is coupled to the system bus 530, but may be connected by other interface and bus structures, such as a parallel port, game port or the USB port 542.

[0073] Information, such as text, images, audio, video, graphics, alerts, and the like, may be presented to a user via one or more presentation devices, such as a monitor 566, a printer 567, and/or a speaker 568. Other presentation devices not shown in FIG. 8 may include a projector, a vibrating component, or the like. These and other presentation devices may be coupled to the processing unit 520 through a video interface 569 (e.g., for a monitor 566 or a projector) and/or an output peripheral interface 570 (e.g., for a printer 567, a speaker 568, and/or a vibration component) that are coupled to the system bus 530, but may be connected by other interface and bus structures, such as a parallel port, game port or the USB port 542. In some examples, the presentation device is integrated with an input device configured to receive information from the user (e.g., a capacitive touch-screen panel, a controller including a vibrating component). Note that the monitor 566 and/or touch screen panel may be physically coupled to a housing in which the computer 510 is incorporated, such as in a tablet-type personal computer.

[0074] The computer 510 may operate in a networked environment using logical connections to one or more remote computers, such as a remote computer 580. The remote computer 580 may be a personal computer (PC), a server, a router, a network PC, a peer device or other common network node, and typically includes many or all of the elements described above relative to the computer 510, although only a memory storage device 581 has been illustrated in FIG. 8. The logical connections depicted in FIG. 8 include one or more local area networks (LANs) 582 and one or more wide area networks (WANs) 583, but may also include other networks. Such networking environments are commonplace in offices, enterprise- wide computer networks, intranets and the Internet.

[0075] When used in a LAN networking environment, the computer 510 is coupled to the LAN 582 through a network interface or adapter 584. When used in a WAN networking environment, the computer 510 may include a modem 585 or other means for establishing communications over the WAN 583, such as the Internet. The modem 585, which may be internal or external, may be connected to the system bus 530 via the user input interface 565 or other appropriate mechanism. A wireless networking component including an interface and antenna may be coupled through a device, such as an access point or peer computer to a LAN 582 or WAN 583. In a networked environment, program modules depicted relative to the computer 510, or portions thereof, may be stored in the remote memory storage device. By way of example, and not limitation, FIG. 8 illustrates remote application programs 586 as residing on memory storage device 581. It may be appreciated that the network connections shown are examples and other means of establishing a communications link between the computers may be used. [0076] The block diagram of FIG. 8 is merely illustrative of an example system that may be used in connection with one or more examples of the disclosure and is not intended to be limiting in any way. Further, peripherals or components of the computing systems known in the art are not shown, but are operable with aspects of the disclosure. At least a portion of the functionality of the various elements in FIG. 8 may be performed by other elements in FIG. 8, or an entity (e.g., processor, web service, applications, server, computing system, etc.) not shown in FIG. 8.

[0077] FIG. 9 is a sequence diagram illustrating example operations 600 for managing BAT activity using various subsystems of the system 100. The system 100 enables one or more stimulators 130 to perform deep brain cooling at various locations of the preoptic area (POA) as the stimulators 130 are systematically or incrementally adjusted until a desired BAT activity is attained. The operations 600 may be performed, for example, one of various modes.

[0078] The operations 600 may be performed under a first or setup mode, for example, when the system 100 is being implanted or positioned (e.g., at the time of surgery). A baseline temperature associated with the BAT 210 is obtained (e.g., via the subject sensor 110) at operation 610 after the subject sensor 110 is positioned to determine whether the subject sensor 110 is in a desired position. In some examples, the baseline temperature is compared with a predetermined baseline temperature threshold for use in systematically or incrementally adjusting the position of the subject sensor 110 until the predetermined baseline temperature threshold is satisfied.

[0079] After the array device 120 is positioned at the target region 210 of the brain, a target test may be performed to determine whether the stimulators 130 are functioning. In some examples, a set of stimulation instructions are provided at operation 612 to the stimulators 130, and one or more stimulated temperatures associated with the stimulators 130 are obtained (e.g., via the target sensors 140) at operation 614. A stimulated temperature may be obtained for each stimulator 130 by identifying a respective target sensor 140 associated with the stimulator 130, and communicating with the identified target sensor 140. [0080] A subject test is performed for each stimulator 130 to determine whether the stimulators 130 are affecting the BAT 210. In some examples, a set of stimulation instructions are provided at operation 616 to the stimulators 130, and one or more test temperatures corresponding to the stimulators 130 are obtained (e.g., via the subject sensors 110) at operation 618. A test temperature may be obtained for each stimulator 130 by communicating with a subject sensor 110 to obtain a temperature associated with the BAT 210 and linking the temperature with the stimulator 130.

[0081] A set of stimulation instructions for the target test and/or subject test includes a stimulator identifier, an ON instruction, an activation time, a wait time, and/or an OFF instruction. During the target test and/or subject test, the stimulators 130 may be activated for a predetermined period of activation time and/or not activated for a predetermined period of wait time. The stimulated temperature and/or test temperature may be obtained a predetermined period of activation time (e.g., 10 minutes) after transmission of a preceding ON instruction. Additionally or

alternatively, an ON instruction may be transmitted a predetermined period of wait time (e.g., 10 minutes) after transmission of a preceding OFF instruction. In some examples, operations of the subject test (e.g., operation 616, operation 618) are distinct from operations of the target test (e.g., operations 612, operation 614).

Alternatively, at least operation may be shared between the subject and the target test. For example, the subject test and target test may both be administered using a common ON instruction.

[0082] In some examples, the test temperatures are compared at operation 620 and, based on the comparison, a stimulator 130 (e.g., a first stimulator) is identified and selected at operation 622. The test temperatures may be compared, for example, with a baseline temperature to identify a difference for each stimulator 130, and the stimulator 130 associated with the greatest difference (as compared to other test temperatures) may be selected. Alternatively, each test temperature may be compared with a respective baseline temperature obtained (e.g., via the subject sensor 110) prior to each transmission of the ON instruction for selecting the stimulator 130 with the greatest difference. [0083] The selected stimulator 130 may be monitored to determine whether the selected stimulator 130 has a desired effect on the BAT 210. In some examples, a set of stimulation instructions are provided at operation 624 to the selected stimulator 130, and one or more monitored temperatures corresponding to the selected stimulator 130 are obtained (e.g., via the subject sensors 110) at operation 626. The monitored temperature may be obtained by transmitting an ON instruction to the selected stimulator 130, identifying a target sensor 140 associated with the selected stimulator 130, communicating with the identified target sensor 140 to obtain a monitored temperature associated with the BAT 210, and transmitting an OFF instruction to the selected stimulator 130. The monitored temperatures may be obtained at one or more predetermined intervals (e.g., 5 minutes and 10 minutes after transmission of the ON instruction). In some examples, the monitored temperature is compared with a predetermined monitored temperature threshold for use in re-positioning the array device 120 and/or re-performing the subject test until the monitored temperatures are within the predetermined range.

[0084] The operations 600 may be performed under a second or configure mode, for example, when the system 100 is being configured or adjusted (e.g., in an outpatient setting). A core temperature associated with the POA is obtained (e.g., via a first target sensor 230) at operation 628 to determine whether the POA is in a desired state and/or it is safe to activate the stimulators 130. In some examples, the core temperature is compared with one or more stimulated temperatures (e.g., obtained via a target test), and a subject test is performed for a stimulator 130 on condition that a stimulated temperature is between about 2.0 °C and about 4.0 °C, inclusive, less than the core temperature. Alternatively, the core temperature may be compared with a predetermined core temperature threshold for use in determining whether to perform one or more target tests and/or subject tests.

[0085] If it is determined safe to activate a stimulator 130, one or more BAT temperatures corresponding to the stimulator 130 are obtained (e.g., via the subject sensors 110) to determine whether the stimulators 130 are affecting the BAT 210. BAT temperatures may include, for example, a baseline temperature (e.g., obtained via operation 610 and/or prior to activation of the stimulator 130) and a test temperature (e.g., obtained at operation 618 and/or after a predetermined period of activation time, such as 5 minutes). In some examples, a single baseline temperature is obtained for all the stimulators 130. Alternatively, a respective baseline temperature may be obtained for each stimulator 130.

[0086] The BAT temperatures are compared at operation 620 to identify a difference for each stimulator 130, and the stimulator 130 associated with the greatest difference (as compared to other test temperatures) is identified and selected at operation 622. The test temperatures, for example, may be compared with the baseline temperature. In some examples, a test temperature is stored for later use or comparison on condition that the test temperature is 0.5 °C greater than the baseline temperature.

[0087] The BAT temperatures are compared at operation 620 to identify a difference for each stimulator 130, and the stimulator 130 associated with the greatest difference (as compared to other test temperatures) is identified and selected at operation 622. The test temperatures, for example, may be compared with the baseline temperature. In some examples, a test temperature is stored for later use or comparison on condition that the test temperature is 0.5 °C greater than the baseline temperature.

[0088] For the selected stimulator 130, one or more monitored temperatures corresponding to the stimulator 130 are obtained (e.g., via the subject sensor 110) at operation 626 to determine whether the selected stimulator 130 has a desired effect on the BAT 210. In some examples, a monitored temperature is compared with a predetermined monitored temperature threshold. If the monitored temperature is 1.0 °C less than or equal to the baseline temperature, then one or more BAT temperatures may be re-obtained until the monitored temperatures are within the predetermined range. A monitored temperature may be obtained, for example, after a predetermined amount of activation time (e.g., 10 minutes).

[0089] Under a third or use mode, the core temperature, stimulated temperature, BAT temperatures, and/or monitored temperatures are monitored. If the core temperature does not satisfy a predetermined threshold (e.g., if the core temperature is greater than 37.5 °C), an OFF instruction is transmitted to the selected stimulator 130. On the other hand, if the core temperature satisfies the predetermined threshold (e.g., if the core temperature is less than or equal to 37.5 °C), then the selected stimulator 130 may be re-activated or activation of the selected stimulator may resume. In some examples, the system 100 may periodically (e.g., weekly) perform one or more operations under the second mode to configure or adjust the system 100 for improving operability of the system 100.

[0090] Example methods and systems are described herein for managing activity of brown adipose tissue. The examples described herein provide a powerful, sustainable influence on the brown adipose tissue. The effects of deep brain cooling are local, definable, and understandable. In this manner, the examples described herein may have broad application for brain modulation for numerous conditions and disorders, including movement disorders, psychiatric disorders, pain, epilepsy, etc.

[0091] Although described in connection with an example computing system environment, examples of the disclosure are capable of implementation with numerous other general purpose or special purpose computing system environments, configurations, or devices. Examples of well-known computing systems,

environments, and/or configurations that may be suitable for use with aspects of the disclosure include, but are not limited to, mobile devices, tablets, laptop computers, desktop computers, server computers, microprocessor-based systems, multiprocessor systems, programmable consumer electronics, communication devices in wearable or accessory form factors, portable media players, gaming consoles, set top boxes, kiosks, tabletop devices, industrial control devices, minicomputers, mainframe computers, network computers, distributed computing environments that include any of the above systems or devices, and the like.

[0092] Examples of the disclosure may be described in the general context of computer-executable instructions, such as program modules, executed by one or more computers or other devices in software, firmware, hardware, or a combination thereof. The computer-executable instructions may be organized into one or more computer-executable components or modules. Generally, program modules include, but are not limited to, routines, programs, objects, components, and data structures that perform particular tasks or implement particular abstract data types. Aspects of the disclosure may be implemented with any number and organization of such components or modules. For example, aspects of the disclosure are not limited to the specific computer-executable instructions or the specific components or modules illustrated in the figures and described herein. Other examples of the disclosure may include different computer-executable instructions or components having more or less functionality than illustrated and described herein.

[0093] In some examples, the operations illustrated in the drawings may be implemented as software instructions encoded on a computer readable medium, in hardware programmed or designed to perform the operations, or both. For example, aspects of the disclosure may be implemented as a system on a chip or other circuitry including a plurality of interconnected, electrically conductive elements.

[0094] The order of execution or performance of the operations in examples of the disclosure illustrated and described herein is not essential, unless otherwise specified. That is, the operations may be performed in any order, unless otherwise specified, and examples of the disclosure may include additional or fewer operations than those disclosed herein. For example, it is contemplated that executing or performing a particular operation before, contemporaneously with, or after another operation is within the scope of aspects of the disclosure.

[0095] The examples illustrated and described herein as well as examples not specifically described herein but within the scope of aspects of the disclosure constitute example means for managing activity of brown adipose tissue. For example, the elements illustrated in FIGS. 1, 2, and 7-9, when programmed, encoded, or configured to perform the operations illustrated in FIGS. 3 and 8, constitute at least an example means for activating a plurality of thermodes (e.g., stimulator 130, target component 430), an example means for receiving a plurality of test temperatures associated with BAT 210 (e.g., subject sensor 110, subject component 420), an example means for selecting a first thermode from the plurality of thermodes for managing activity of the BAT 210 (e.g., interface component 410, hub component 440), and an example means for monitoring the first thermode (e.g., stimulator 130, target sensor 140, interface component 410, target component 430, hub component 440).

EXAMPLES

[0096] Experiments were performed in accord with the regulations detailed in the Guide for the Care and Use of Laboratory Animals: Eight Edition (National Research Council, National Academies Press, 2010) and were approved by the Animal Care and Use Committee of the Oregon Health and Science University.

[0097] Studies were done in 38 male Sprague-Dawley rats (300-375g). Under isoflurane anesthesia (3% in 100% 0₂), the right femoral artery and vein were cannulated for measurements of arterial pressure and systemic drug injections, respectively, and a tracheotomy was performed to insert an endotracheal tube for artificial ventilation. Following venous cannulation animals were transitioned to urethane and a-chloralose anesthesia (750 mg/kg and 60 mg/kg iv, respectively). Subsequently, rats were mounted in a stereotaxic apparatus (David Kopf Instruments) with a spinal clamp on the T8-T9 vertebral processes and the incisor bar positioned at -12.0 mm. Rats were artificially ventilated (100% O2) and paralyzed with d- tubocurarine (3mg/kg, iv). Expired CO2 was continuously monitored. A water- perfused thermal blanket containing silicone tubing was wrapped around the rat's shaved trunk from the shoulders to the hips to produce changes in skin temperature (TSKIN) by perfusing the blanket with cold or warm water. Thermocouples were fixed into the rectum for measurement of TCORE, into the left interscapular BAT pad for BAT temperature (TBAT), and to the shaved abdominal skin surface under the thermal blanket for TSKIN. Craniotomies overlying the target brain regions were performed to permit the insertion of the bilateral POA cooling thermodes (FIGS. IOC, 10D), a thermocouple positioned ~0.5mm caudal to the tip of the silver rod to measure the preoptic area temperature (TPOA), and of the nanoinjection micropipettes.

[0098] A custom built thermode, consisting of two silver rods (0.5mm diameter, and extending ~15mm from attachment to the peltier devices) sandwiched between two peltier devices (TE Technology Inc., MI, USA), and external metal plates to serve as heat sinks, was used to cool the POA bilaterally. With the thermode angled so that the rods were approximately perpendicular to the skull surface, the silver rods were inserted into the preoptic area, bilaterally, (coordinates from bregma: +0.5 mm anterior; -/+1.5 mm lateral and -8.4 mm ventral from dura, FIGS. IOC, 10D). The peltier devices were connected to a DC power supply (Model 1735A, BK Precision, USA) for passing current (0.2 to 0.3 Amp) to induce decreases in brain temperature. Due to the thermal conductivity of brain tissue, temperature gradients are induced around a thermode, therefore the cooling protocol decreases the local temperature for several millimeters around the thermodes, making it difficult to assess the precise location of the critical temperature-sensitive neurons affected by the cooling protocol. Nonetheless, the area containing thermosensitive neurons has been documented and in the current study the largest responses to brain cooling were obtained when the thermodes were inserted into the POA at a depth of at least 8mm ventral to dura. In contrast, cooling superficial areas of the brain with the thermodes inserted only a couple millimeters ventral to dura yielded little to no activation of BAT SNA and thermogenesis. Therefore, this cooling protocol is referred to as POA cooling.

[0099] In the initial POA cooling experiment (FIGS. 10A, 10B), the control TPOA was lower than TCORE, possibly due to the heat-sink capacity of the thermodes within the POA. Therefore, in all subsequent experiments, a small current of the polarity opposite to that causing cooling, was passed to the peltier device during control periods to maintain TPOA at a stable temperature of 35-36°C, which did not result in any activation of BAT SNA (FIGS. 10A, 10B). The peltier polarity was subsequently reversed to initiate POA cooling.

[00100] Bipolar hook electrodes were used to record the activity on small nerve bundles dissected from the ventral surface of the right interscapular BAT pad. BAT SNA was amplified (xlOK, bandpass: 1-300 Hz, CyberAmp 380; Axon

Instruments, USA) and digitized (Spike 2; Cambridge Electronic Design) to a hard drive along with all other variables. A continuous measurement (4s bins) of BAT SNA amplitude was obtained from the autospectra of sequential 4s segments of raw BAT SNA as the root mean square value (square root of the total power in the 0.1 to 20 Hz frequency band) of the BAT SNA.

[00101] To initially verify the viability of the dissected nerve bundles, skin cooling evoked increases in BAT SNA were tested by perfusing cold water through the thermal blanket, or by turning off the heat lamp. Following this initial test, to ensure conditions in which there is little to no BAT SNA, TCORE was maintained above 36.5°C, with the use of an infrared heating lamp and by perfusing warm water through the thermal blanket.

[00102] Drugs were nanoinjected (60nl) into the median preoptic nucleus (MnPO; coordinates: from bregma: 0.0 mm rostral, on the midline and 6.4 mm ventral to dura), the dorsomedial hypothalamus (DMH; 3.2 mm caudal and 0.5 mm lateral to bregma, and 8.2 mm ventral to dura); or the raphe pallidus area (RPa; 3.0 mm caudal to lambda, on the midline, and 9.5 mm ventral from dura). The observation of an increase in BAT SNA and TBAT in response to nanoinjection of N-methyl-D-aspartate (NMD A, 0.2mM, 60nl) in MnPO was used to precisely localize the appropriate MnPO site. The following drugs were subsequently nanoinjected into MnPO: (2R)- amino-5-phosphonovalericacid (AP5, 5 mM) combined with 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX; 5mM, 60nl) or buffered saline (0.9% sodium chloride sterile, 60nl). AP5/CNQX (5mM each in 60nl) was also injected into DMH (bilateral) and into the RPa during POA cooling. Fluorescent polystyrene

microspheres (FluoSpheres, F8797, F8801 or F8803; Molecular Probes) were included in the injected drug solutions (1 : 100 volume dilution of FluoSpheres in the injectate) to allow histological identification of the drug nanoinjection sites.

[00103] Histology. At the end of the experimental procedures, rats were transcardially perfused with 5% formaldehyde. Brains were removed and placed in 30% sucrose solution overnight and sliced (60 μπι coronal sections) using a microtome. Drug injection sites and thermode tracts were identified in sections and plotted on schematic drawings. [00104] Data Analysis. Spike2 software (Cambridge Electronic Design, UK) was used to digitize analogue signals that were acquired during experiments. Mean arterial pressure (MAP) and heart rate (HR) were obtained from the pulsatile arterial pressure signal. For each experiment, the baseline (BL) level of BAT SNA was determined as the mean BAT SNA during a period when the rat was in a warm condition (TCORE and TSKIN > 36.5°C) and basal bursting of BAT SNA was absent (i.e., 100% BL BAT SNA is approximately equal to no ongoing BAT SNA).

[00105] For all recorded variables, a repeated measures ANOVA was used to compare the mean control values during the 30 second period prior to POA cooling, the mean control values during the 30 second periods prior to nanoinjections or termination of the POA cooling, and the 30s mean values at a time point 5 minutes after the nanoinjection or termination of the POA cooling or 10 minutes after the nanoinjections (for MnPO injections). To assess the drug treatment effects, paired t- tests were performed using StatPlus, comparisons were made between the drug- injected and vehicle-injected trials at each of the time points: 30 seconds control prior to cooling, during cooling (30 seconds prior to nanoinjection), and 30 second period beginning 5 or 10 minutes after nanoinjection. Group data were given as mean ± SE. An alpha level of 0.05 was used to determine significance.

[00106] Under control conditions in urethane-chloralose anesthetized rats with TSKIN at 36.7 ± 0.5 °C and TCORE at 36.4 ± 0.6 °C, BAT SNA was low (FIG. 10A, Table 1). Likely due to the intrinsic thermal properties of the thermode to act as a heat sink and the general effect of anesthesia to decrease brain temperature, the control TPOA (33.9± 0.4 °C) was lower than TCORE and TSKIN. Passing current to the peltier device produced a rapid reduction in TPOA, leading to an increase in BAT SNA (FIGS. 10A, 10B), with activity beginning when T_POA had fallen by -1.3 ± 0.3 °C (range: -0.4°C to -2.8°C). Cooling the POA (FIGS. 10E, 10F) also increased TBAT, expired C0₂, and HR (FIG. 10). The values of the recorded variables 10 minutes after beginning POA cooling, at a time when TPOA had stabilized at 30.2 ± 0.6 °C, are provided in Table 1. TSKIN and TCORE were not changed during the 10 minutes of POA cooling (Table 1). Termination of the thermode-evoked cooling of the POA returned all measured variables to the control levels within ten minutes (FIGS. 10A, 10B, Table 1). Sustained POA cooling increased BAT SNA, TBAT, expired C0₂, and HR for at least one hour (FIGS. IOC, 10D).

Table 1. Effect of thermode-induced POA cooling.

Values for preoptic area temperature (TPOA), brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (TBAT), expired carbon dioxide (Exp. CO2), heart rate (HR), mean arterial pressure (MAP), core temperature (TCORE), and skin temperature (TSKIN), before POA cooling (pre-POA cooling), during cooling (10 minutes after beginning of cooling), and 10 minutes after terminating the cooling (post-POA cooling). * Significantly different from the pre-cooling values (p<0.05).

[00107] The RPa contains the sympathetic premotor neurons for BAT and the glutamatergic activation of these neurons is necessary for many stimuli that increase BAT SNA. Whether the glutamatergic activation of neurons in the RPa was necessary for the responses evoked by POA cooling was determined by injecting a cocktail of the ionotropic glutamate receptor antagonists, AP5 and CNQX, into the RPa (FIG. 11C) during the thermode-evoked cooling of the POA. With TSKIN and TCORE initially above 37 °C, reducing TPOA by 4-5 °C increased BAT SNA, TBAT, expired C0₂, and HR (FIGS. 11A, 1 IB; Table 2). After 5 minutes of cooling, nanoinjection of AP5/CNQX into the RPa rapidly and completely reversed the increases in BAT SNA, TBAT, expired C0₂, and HR evoked by cooling the POA (FIG. 1 IB, Table 2). AP5/CNQX in the RPa also decreased MAP below the control level prior to POA cooling (FIG. 1 IB). In contrast, saline vehicle injection in the RPa did not affect the elevated levels of BAT SNA, TBAT, expired C0₂, HR evoked by POA cooling (FIG. 11B, Table 2).

Table 2. Effect of glutamate receptor blockade in RPa on POA cooling-evoked responses.

Values for preoptic area temperature (TPOA), brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (TBAT), expired carbon dioxide (Exp. C0₂), heart rate (HR), mean arterial pressure (MAP), core temperature (TCORE), and skin temperature (TSKIN), before POA cooling, during cooling (5 min after beginning cooling), and 5 minutes after injection of either saline vehicle or AP5/CNQX in the raphe pallidus (RPa.). * Significantly different from the pre-cooling values (p<0.05), + significantly different from vehicle treated group.

[00108] The DMH has been suggested to provide a necessary glutamatergic input to neurons in the RPa for the activation of BAT induced by several stimuli. Having demonstrated that a glutamatergic input to the RPa was necessary for the POA cooling-evoked increase in BAT SNA (FIG. 11), whether the activation of neurons in the DMH would also be necessary for this response was determined. To determine whether the glutamatergic activation of neurons in the DMH was necessary for the responses evoked by cooling the POA, saline vehicle or a combination of the ionotropic glutamate receptor antagonists, AP5 and CNQX, was injected into the DMH (FIG. 12C) during the thermode-evoked cooling of the POA. The POA cooling- evoked increases in BAT SNA, TBAT, expired C0₂, and HR, did not differ between trials in which vehicle or AP5/CNQX were subsequently nanoinjected (FIG. 12B). Bilateral nanoinjections of AP5/CNQX (FIG. 12A) into the DMH completely reversed the increases in BAT SNA evoked by cooling the POA and also decreased TBAT, expired CO2, HR and MAP from the peak POA cooling-evoked levels (FIGS. 12A, 12B; Table 3). In contrast, bilateral nanoinjections of vehicle did not affect the elevated levels of BAT SNA, TBAT, expired C0₂, HR evoked by POA cooling (FIG. 12B, Table 3), resulting in significant differences in these variables between the AP5/CNQX-injected and vehicle-injected groups at 5 minutes after the nanoinjections in the DMH (FIG. 12B, Table 3).

Table 3. Effect of glutamate receptor blockade in DMH on POA cooling-evoked responses.

Values for preoptic area temperature (TPOA), brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (TBAT), expired carbon dioxide (Exp. C0₂), heart rate (HR), mean arterial pressure (MAP), core temperature (TCORE), and skin temperature (TSKIN), before POA cooling, during cooling (5 min after beginning cooling), and 5 minutes after injection of either saline vehicle or AP5/CNQX in the dorsomedial hypothalamus (DMH). * Significantly different from the pre-cooling values (p<0.05), + significantly different from vehicle treated group.

[00109] To determine whether the activity of neurons in the MnPO was necessary for the responses evoked by cooling the POA, saline vehicle, the GABAA receptor agonist, muscimol (muse), or a combination of the ionotropic glutamate receptor antagonists, AP5 and CNQX, was injected into the MnPO (FIGS. 13D and 13E) during the thermode-evoked cooling of the POA. Under warm conditions, with TSKIN and TCORE maintained above 37°C the POA cooling-evoked increases in BAT SNA, TBAT, expired CO2, and HR that did not differ between injection groups (FIG. 13C). Nanoinjection of AP5/CNQX or muse into the MnPO completely reversed the increases in BAT SNA TBAT, expired CO2, and HR evoked by cooling the POA (FIG. 13, Table 4). In contrast, bilateral nanoinjections of vehicle in the MnPO did not affect the elevated levels of BAT SNA, TBAT, expired C0₂, HR evoked by POA cooling (FIG. 13C). Ten minutes after the nanoinjections in the MnPO, BAT SNA, TBAT, expired CO2, and HR were significantly different between the vehicle-injected and both the AP5/CNQX-injected and muscimol-injected groups (FIG. 13C, Table 4). Table 4. Effect of muscimol and AP5/CNQX in MnPO on POA cooling-evoked

response.

Values for preoptic area temperature (TPOA), brown adipose tissue (BAT) sympathetic nerve activity (SNA), BAT temperature (TBAT), expired carbon dioxide (Exp. CO2), heart rate (HR), mean arterial pressure (MAP), core temperature (TCORE), and skin temperature (TSKIN), before POA cooling, during cooling (5 min after beginning cooling), and 10 minutes after injection of either saline vehicle, muscimol, or AP5/CNQX in the median preoptic nucleus (MnPO). * Significantly different from the pre-cooling values (p<0.05), + significantly different from vehicle treated group.

[00110] A major finding presented in the Examples is that POA cooling increased BAT SNA and BAT thermogenesis through a canonical BAT

sympathoexcitatory pathway that included a glutamatergic excitation of

therm ogenesis-promoting neurons in the DMH and a glutamatergic excitation of BAT sympathetic premotor neurons in the RPa. These Examples also revealed a requirement for a glutamatergic activation of neurons in the MnPO in the POA cooling-evoked BAT activation.

[00111] First, the increases in BAT SNA and BAT thermogenesis evoked by POA cooling required glutamatergic activation of neurons in the RPa, thus paralleling the requirement for glutamatergic activation of putative sympathetic premotor neurons for BAT in the RPa for a number of stimuli that increase BAT SNA including skin cooling. Glutamatergic input to the DMH was also required for the POA-cooling evoked increase in BAT SNA and BAT thermogenesis, paralleling the fundamental neurocircuitry for febrile activation of BAT. Surprisingly, whether glutamatergic input to the DMH was also required for skin cooling evoked activation of BAT was unknown.

[00112] Finally, glutamatergic activation of neurons in the MnPO was also necessary for the POA cooling-evoked increase in BAT SNA and BAT

thermogenesis. This parallels the finding that glutamate receptor activation in the MnPO was necessary for the increase in BAT SNA evoked by activation of the cutaneous cold afferent pathway, however the source of the glutamatergic input to neurons in the MnPO that is required for the local POA cooling response likely differs from that during the skin cooling response. During skin cooling neurons in the external lateral subregion of the lateral parabrachial nucleus (LPBel) were activated by cutaneous cold afferent input and provide a glutamatergic input to the MnPO. In contrast, in the current Examples TSKIN was maintained at a temperature at which cold responsive neurons in the LPBel would have a low firing rate, indicating that the glutamatergic input to neurons in the MnPO during local POA cooling was likely to originate from another source, perhaps from local interneurons.

[00113] Of particular interest is the result that a glutamatergic drive activated BAT during POA cooling. This finding indicates that the glutamatergic input to BAT sympathoexcitatory, DMH neurons required for the BAT activation during POA cooling may arise from glutamatergically-driven, potentially "cold- responsive" neurons in the MnPO.

[00114] The largest responses to brain cooling were obtained when the thermodes were inserted into the POA at a depth of at least 8mm ventral to dura. In contrast, cooling superficial areas of the brain with the thermodes inserted only a couple millimeters ventral to dura yielded little to no activation of BAT SNA and thermogenesis.

[00115] The Examples demonstrate that robust increases in BAT SNA and BAT thermogenesis and metabolism can be elicited from local cooling in the POA even in the face of warm thermal inputs from the skin and the body core.

[00116] When introducing elements of aspects of the disclosure or the examples thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. Furthermore, references to an "embodiment" or "example" of the present disclosure are not intended to be interpreted as excluding the existence of additional embodiments or examples that also incorporate the recited features. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. The phrase "one or more of the following: A, B, and C" means "at least one of A and/or at least one of B and/or at least one of C."

[00117] Having described aspects of the disclosure in detail, it will be apparent that modifications and variations are possible without departing from the scope of aspects of the disclosure as defined in the appended claims. As various changes could be made in the above constructions, products, and methods without departing from the scope of aspects of the disclosure, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

[00118] While the aspects of the disclosure have been described in terms of various examples with their associated operations, a person skilled in the art would appreciate that a combination of operations from any number of different examples is also within the scope of the aspects of the disclosure.

Claims

WHAT IS CLAIMED IS:

1. A method for managing activity of brown adipose tissue, the method comprising:

positioning a subject sensor proximate to the brown adipose tissue;

positioning an array device proximate to a preoptic area, the array device including a plurality of stimulators;

activating the plurality of stimulators;

receiving, from the subject sensor, a plurality of test temperatures associated with the brown adipose tissue, each test temperature of the plurality of test temperatures corresponding to a respective stimulator set of the plurality of stimulators; and

based on the plurality of test temperatures, selecting, from the plurality of stimulators, a first stimulator for managing the activity of the brown adipose tissue.

2. The method of claim 1, wherein activating the plurality of stimulators comprises sequentially activating the plurality of stimulators, each stimulator of the plurality of stimulators activated for a predetermined period of activation time.

3. The method of claim 1, wherein activating the plurality of stimulators comprises waiting a predetermined period of wait time between activating the first stimulator and activating a second stimulator of the plurality of stimulators.

4. The method of claim 1, wherein receiving the plurality of test temperatures comprises receiving a first test temperature of the plurality of test temperatures corresponding to the first stimulator within a predetermined time frame of the first stimulator being activated.

5. The method of claim 1 further comprising:

receiving, from the subject sensor, a baseline temperature associated with the brown adipose tissue; and

comparing the plurality of test temperatures with the baseline temperature.

6. The method of claim 1 further comprising: receiving, from a plurality of target sensors included in the array device, a plurality of first temperatures associated with the plurality of stimulators;

receiving, from the plurality of target sensors, a plurality of second temperatures associated with the plurality of stimulators; and

comparing the plurality of second temperatures with the plurality of first temperatures.

7. The method of claim 1 further comprising:

receiving, from a first target sensor included in the array device, a core temperature associated with the preoptic area;

receiving, from a plurality of second target sensors included in the array device, a plurality of first temperatures associated with the plurality of stimulators; and

comparing the plurality of first temperatures with the core temperature.

8. The method of claim 1 further comprising:

determining whether the plurality of test temperatures satisfy a predetermined test threshold; and

on condition that the predetermined test threshold is not satisfied,

repositioning the array device.

9. The method of claim 1 further comprising:

activating the first stimulator;

receiving, from the subject sensor, a first temperature associated with the brown adipose tissue; and

determining whether the first temperature satisfies a predetermined temperature threshold;

on condition that the predetermined temperature threshold is not satisfied, selecting, from the plurality of stimulators, a second stimulator for managing the activity of the brown adipose tissue.

10. The method of claim 1 further comprising:

receiving, from a target sensor included in the array device, a core temperature associated with the preoptic area;

determining whether the core temperature satisfies a predetermined temperature threshold; and

on condition that the predetermined temperature threshold is not satisfied, generating an alert and waiting a predetermined period of wait time.

11. A system for managing activity of brown adipose tissue, the system comprising:

a subject component comprising a sensor that detects a temperature associated with the brown adipose tissue;

a target component comprising a plurality of stimulators that systematically stimulate a preoptic area; and

a hub component coupled to the subject component and to the target component, the hub component configured to monitor the temperature associated with the brown adipose tissue and, based on the monitored temperature, select a first stimulator from the plurality of stimulators for managing the activity of the brown adipose tissue.

12. The system of claim 11, wherein the target component is configured to sequentially activate the plurality of stimulators, each stimulator of the plurality of stimulators activated for a predetermined period of activation time.

13. The system of claim 11, wherein the target component is configured to wait a predetermined period of wait time between activating the first stimulator and activating a second stimulator of the plurality of stimulators.

14. The system of claim 11, wherein the hub component is configured to identify a first test temperature corresponding to the first stimulator within a predetermined time frame of the first stimulator being activated.

15. The system of claim 11, wherein the hub component is configured to identify a baseline temperature associated with the brown adipose tissue, identify a plurality of test temperatures associated with the brown adipose tissue, and compare the plurality of test temperatures with the baseline temperature, each test temperature of the plurality of test temperatures corresponding to a respective stimulator set of the plurality of stimulators.

16. The system of claim 11, wherein the hub component is configured to identify a plurality of first temperatures associated with the plurality of stimulators, identify a plurality of second temperatures associated with the plurality of stimulators; and compare the plurality of second temperatures with the plurality of first temperatures.

17. The system of claim 11, wherein the hub component is configured to identify a core temperature associated with the preoptic area, identify a plurality of first temperatures associated with the plurality of stimulators; and compare the plurality of first temperatures with the core temperature.

18. The system of claim 11, wherein the hub component is configured to identify a core temperature associated with the preoptic area, determine whether the core temperature satisfies a predetermined temperature threshold, and, on condition that the predetermined temperature threshold is not satisfied, generate an alert.

19. The system of claim 11, wherein the target component is configured to determine whether a core temperature associated with the preoptic area satisfies a predetermined temperature threshold, and, on condition that the predetermined temperature threshold is not satisfied, wait a predetermined period of wait time.

20. An assembly for managing activity of brown adipose tissue, the assembly comprising:

a subject thermistor, the subject thermistor positionable proximate to the brown adipose tissue;

an array device comprising a plurality of thermodes and one or more target thermistors proximate to the plurality of thermodes, the plurality of thermodes positionable proximate to a preoptic area; and

a control system coupled to the subject thermistor and to the array device, the control system configured to activate the plurality of thermodes, receive a plurality of test temperatures associated with the brown adipose tissue from the subject thermistor, select a first thermode from the plurality of thermodes based on the plurality of test temperatures for managing the activity of the brown adipose tissue, and monitor the first thermode using the one or more target thermistors, each test temperature of the plurality of test temperatures corresponding to a respective thermode set of the plurality of thermodes.