This study was supported by the Canadian Institutes of Health Research.

All the methods described in this protocol have been approved by Conjoint Health Research Ethics Board, University of Calgary (REB16-2474). The protocol is described in Figure 1.
1. Non-invasive brain stimulation contraindications
<ol>
	<li>Screen all participants for contraindications for TMS15 and tDCS1 prior to recruitment.</li>
</ol>
2. Transcranial magnetic stimulation motor mapping
<ol>
	<li>Preparing MRI for navigated TMS
	<ol>
		<li>Obtain each participant&#8217;s structural MRI (T1). If an MRI is unobtainable, use a template MRI from Montreal Neurological Institute.</li>
		<li>Import the MRI file in DICOM or NIFTI format to the neuronavigation software (see Table of Materials).</li>
	</ol>
	</li>
	<li>TMS target trajectories
	<ol>
		<li>Use the neuronavigation software to reconstruct Skin and Full Brain Curvilinear using the tabs.</li>
		<li>Select New, Skin, and Compute Skin. Ensure the nose and top of the head are included.</li>
		<li>Select New, and Full Brain Curvilinear. Enclose the green selection box outside of the brain but inside of the skull. Select Compute Curvilinear. Adjust the peel depth to 4.0-6.0 mm.</li>
		<li>Select Configure Landmarks. Place four landmarks at the tip of nose, nasion, and the notches of both ears of the reconstructed skin. Name the landmarks corresponding to their anatomy.</li>
		<li>Select the Targets tab to view curvilinear brain. Select New, and Rectangular Grid. Place uniform 12 x 12 coordinate grids with 7 mm spacing on the surface of the reconstructed brain over the &#8220;handknob&#8221; of the motor cortex (precentral gyrus)17.</li>
		<li>Use the Target Positioning Tool on the right to optimize the grid positioning for rotation, tilt, and curvature. Convert the grid-points into trajectories that will guide the robot to position the TMS coil. Adjust the angle of the trajectories so they are 45&#176; to the longitudinal fissure of the brain.</li>
		<li>Use the SNAP tool to extrapolate and optimize the trajectories to curvilinear brain.</li>
		<li>Initialize and position the TMS robot arm and seat to Welcome position and calibrate the force plate sensor using Force sensor test.</li>
	</ol>
	</li>
	<li>Preparing the participant for motor mapping 
	<ol>
		<li>Have the participants fill out a safety questionnaire18.</li>
		<li>Once the participants seated comfortably in the robot chair, adjust the backrest and neckrest.&#160;Ensure their feet are supported. Support their arms and hands with pillows to ensure their hands are in a resting position for the duration of the mapping session. 
		NOTE: Children and adolescents will need reminders throughout the session to keep their hands relaxed.</li>
		<li>Clean the skin over the muscle of interest. Place Ag/AgCl surface electrodes on both hands and forearms of the participant, targeting four distal forelimb muscles, 1) the belly of the first dorsal interosseous (FDI), 2) abductor pollicis brevis (APB), 3) abductor digiti minimi (ADM), and 4) the wrist extensor (extensor carpi ulnaris).</li>
		<li>Connect the surface electrodes with electromyography (EMG) amplifier and data acquisition system and connect the amplifier to a data collecting computer with a compatible EMG software.</li>
		<li>Co-register the four landmarks on the head of the participant using the landmark pointer. Use the validation tab to ensure the participant&#8217;s head is properly registered.</li>
	</ol>
	</li>
	<li>Determining motor mapping TMS intensity
	<ol>
		<li>Select a grid-point closest to the participant&#8217;s &#8220;handknob&#8221;. Select the Align to Target button to align the TMS coil held by the robot to this target location. Select Contact on. Monitor the contact quality using the contact force indicator. Ensure the indicator is green or yellow. 
		NOTE: The red color on the contact indicator means there is too much force on the participant&#8217;s head. No color means the TMS coil is not in contact with the participant&#8217;s head. In these cases, adjust the force plate sensitivity.</li>
		<li>Instruct the participant not to move outside the scope of the robot arm. Ensure the participant&#8217;s hand muscles are relaxed and remain still prior to contact.</li>
		<li>Select Align and Follow so the coil remains centered on the target if the participant moves.</li>
		<li>Use the TMS trigger button on the TMS machine to deliver 5-10 TMS pulses at an intensity between 40-60% maximum stimulator output (MSO). Repeat this step to 5-6 grid-points surrounding the &#8220;handknob&#8221;.</li>
		<li>Determine the grid-point that gives the largest and most consistent (hotspot) motor evoked potential (MEP) for the left or right FDI muscle.</li>
		<li>Determine the Resting Motor Threshold (RMT) as the lowest intensity that produces an MEP of at least 50 &#181;V in the FDI muscle in 5/10 stimulations.</li>
	</ol>
	</li>
	<li>Motor mapping 
	<ol>
		<li>Starting from the grid-point closest to the hotspot, deliver four single-pulse TMS pulses (1 Hz) at an interstimulus of 1 s and TMS intensity of 120% RMT. A responsive grid-point is determined by 2/4 MEPs &#62;50 &#181;V in any of the hand muscles.</li>
		<li>Move to the adjacent grid-point and repeat the above step.</li>
		<li>Continue sequentially in a linear fashion along responsive points until a non-responsive point is reached, which is the first border region of the map.</li>
		<li>Continue mapping to establish the border points in all four directions of the rectangular grid.</li>
		<li>Record all MEPs from all muscles using the EMG software for offline analysis.</li>
		<li>After 3-4 grid points, select Contact off and give the participant a break until they feel ready to continue.</li>
		<li>Throughout the mapping session, continuously check in with the participant to ensure they are comfortable and/or need a break.</li>
		<li>Use a hard copy version of the same grids to tack the simulation order for further analysis.</li>
		<li>Complete mapping using a robotic TMS as described here or manually (not described in this manuscript). If using a TMS Robot, it will move to the grid-point selected by the experimenter. The robot will accommodate for child head motion in near real time. This will alleviate any additional movement associated with a technician manually holding the coil on the participant&#8217;s head. 
		NOTE: If mapping using a TMS robot, ensure there is an experimenter beside the robot at all times during the session. If the robot is placed on a participant&#8217;s head and the participant suddenly moves, the robot will try to follow their head. If the participant must move, sneeze, scratch, or perform an activity involving the movement of their head, the robot arm must be moved to prevent the participant&#8217;s head from hitting the robot&#8217;s arm or TMS coil.</li>
	</ol>
	</li>
	<li>Motor map creation 
	<ol>
		<li>Using a custom-made coding script, generate three-dimensional motor maps (Figure 2).&#160;Contact the authors for the script.</li>
		<li>Calculate motor map area and volume using responsive trajectory sites. Calculate center of gravity (COG) as weighted average of the motor representations of each coordinate location. 
		NOTE: Map area is calculated as the grid spacing (7 mm)2 multiplied by the total number of responsive sites. Map volume is calculated as the cumulative sum of grid spacing multiplied by the mean MEP amplitude at each responsive site. A user-friendly version of the script is being developed to share with the public as open source. Meanwhile, contact the corresponding author to get access to the script.</li>
	</ol>
	</li>
</ol>
3. Conventional tDCS and HD-tDCS application
<ol>
	<li>Randomize the participants to one of three intervention groups (sham, conventional tDCS, HD-tDCS).</li>
	<li>Have the participant complete the Purdue Pegboard Test (PPT) three times using their left hand (non-dominant), establishing their baseline score.</li>
	<li>Inspect electrode quality to confirm the integrity of the tDCS sponge inserts and rubber electrodes.</li>
	<li>Turn on the conventional tDCS device by flipping the power switch to ON. 
	NOTE: Ensure the low battery light is not illuminated. If it is illuminated, change the batteries before starting the session.
	<ol>
		<li>For participants receiving conventional or sham tDCS, lightly soak two 25 cm2 sponge electrodes with saline. Ensure the entire electrode is covered but not dripping. Insert the rubber electrode into the saline soaked sponge electrodes and connect each electrode to the tDCS device.</li>
	</ol>
	</li>
	<li>Locate the marked hotspot (Right M1) using the neuronavigation and mark it with a non-toxic marker. At the end of each tDCS, HD-tDCS or sham session, mark the hotspot again so that it is visible the next day.
	<ol>
		<li>If randomized to conventional tDCS or sham tDCS, place one 25 cm2 saline-soaked sponge electrode over the participant&#8217;s marked hotspot (Right M1), serving as the anode. Place the other 25 cm2 saline-soaked sponge electrode on the contralateral supraorbital region, representing the cathode. Use a light plastic pediatric &#8220;headband&#8221; to hold electrodes in place. 
		NOTE: Ensure that there is no saline dripping from the electrode as it may shunt the current.</li>
		<li>In the sham and conventional tDCS group, ensure &#8220;optimal&#8221; contact quality. If the contact quality is &#8220;sub-optimal&#8221;, inject a small amount of saline solution under the sponge electrodes, or ensure that there is minimal hair between the scalp and electrode. 
		NOTE: &#8220;Optimal&#8221; contact quality is achieved when more than half of the quality of contact indicator lights are on. If less than half of the contact indicator lights are on, the contact quality is sub-optimal. Do not start stimulation if only one of two of the indicator lights are on.</li>
		<li>In the HD-tDCS group, refer to Villamar, M.F., et al.16 for the appropriate set-up.</li>
		<li>In the HD-tDCS group, set the device to the Scan setting to check the impedance at each electrode. Ensure the impedance is under 1 &#8220;quality unit&#8221; and described previously19,20. If contact quality is poor, remove the electrode and check that there is no hair obstructing the contact of the electrode, and that a continuous column of electrode gel is present between the scalp and electrode. If needed, apply more electrode gel.</li>
	</ol>
	</li>
	<li>Set the tDCS and HD-tDCS device to the anode montage setting, 1 mA current strength, and 20 min duration.</li>
	<li>Ensure the participant is sitting comfortably and they understand the possible sensations they may experience (such as itchy or tingling sensations). Remind the participant to communicate if they feel any discomfort or if they have any questions.
	<ol>
		<li>In the conventional tDCS and HD-tDCS groups, make sure the toggle is set to Active. 
		NOTE: For the sham group, the toggle should be set to Sham. This setting should be hidden from the participant.</li>
		<li>Press the device&#8217;s Start button to start stimulation. Ensure the duration is set to 20 min, and the intensity to 1 mA. 
		NOTE: In the conventional tDCS and HD-tDCS groups, the current will ramp up over 30 s to 1 mA and continue for 20 min. In the sham tDCS group, current will be ramped up over 30 s to 1 mA and immediately ramped down over 30 s.</li>
	</ol>
	</li>
	<li>At 5 min, 10 min, 15 min, and 20 min, have the participant complete the PPT three times using their left hand.</li>
	<li>After 20 min, turn the device off after the intensity finishes ramping down to 0 mA. 
	NOTE: For participants receiving either conventional tDCS or HD-tDCS, the machine will automatically ramp down to 0 mA at 20 min. For participants receiving sham tDCS, the machine will automatically ramp up over 30 s to 1 mA and immediately ramp down to 0 mA over 30 s at 20 min.</li>
	<li>Remove the electrodes from the participant&#8217;s head.</li>
	<li>For sham and conventional tDCS group, remove black electrodes from inside the sponges and rinse the sponge electrode with normal tap water.
	<ol>
		<li>In the HD-tDCS group, take off the plastic electrode holder top and remove the electrodes. Remove the electrode cap from participants&#8217; head. Rinse any gel in the electrode holder. Clean the electrode with a slightly damp paper towel. Wipe the electrode with a dry paper towel to remove any remaining gel.</li>
	</ol>
	</li>
	<li>Have all participants complete the Transcranial Direct-Current Stimulation Side-effects and Tolerability questionnaire after each stimulation session.</li>
	<li>Have the participants complete the PPT three times using their left hand.
	<ol>
		<li>Have the participants return the following day and for another four consecutive days (five days total) for non-invasive brain stimulation (sham, tDCS, or HD-tDCS) paired with motor learning (PPT). Repeat steps 3.2-3.13 on Day 2-4. On Day 5, have the participants begin with non-invasive brain stimulation (sham, tDCS or HD-tDCS) (steps 3.2-3.13 are repeated). After a break (45 min-~1.5 h since receiving stimulation), start robotic TMS motor mapping (steps 2.3-2.5.8). 
		NOTE: All participants received the same number of minutes for breaks between assessments.</li>
		<li>After 6-weeks, invite the participants to return and perform the PPT without receiving any non-invasive brain stimulation (step 3.2 followed by robotic TMS motor mapping (step 2.5.8)).</li>
	</ol>
	</li>
</ol>

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The authors have no disclosures.

TMS has also been explored in clinical pediatric populations, including perinatal stroke22 and cerebral palsy, where TMS motor maps were successfully created in children with cerebral palsy to explore mechanisms of interventional plasticity. Using an established protocol8, TMS motor maps were successfully collected in typically developing children, and are currently being collected in an ongoing multicenter clinical trial for children with perinatal stroke and hemiplegic ce...

Non-invasive brain stimulation can both measure and modulate human brain function1,2. The most common target has been the motor cortex, due in part to an immediate and measurable biological output (motor evoked potentials) but also the high prevalence of neurological diseases resulting in motor system dysfunction and disability. This large global burden of disease includes a high proportion of conditions affecting children such as cerebral palsy, the leading cause of lifelong disability affecting some 17 million persons worldwide3. Despite this clinical relevance and the diverse and increasing capacities of neurostimulation technologies, applications in the developing brain are only beginning to be defined4. Improved characterization of existing and emerging non-invasive brain stimulation methods in children are required to advance applications in the developing brain.
Transcranial magnetic stimulation (TMS) is a well-established neurophysiological tool being increasingly used for its non-invasive, painless, well-tolerated and safety profile in adults. TMS experience in children is relatively limited but steadily increasing. TMS delivers magnetic fields to induce regional activation of cortical neuronal populations in the brain with net outputs reflected in target muscle motor evoked potentials (MEP). Systematic application of single pulse TMS can define maps of the motor cortex in vivo. Seminal animal studies5 and emerging human TMS studies6 have shown how motor maps may help inform mechanisms of cortical neuroplasticity. Navigated motor mapping is a TMS technique that is used to map out the human motor cortex to interrogate functional cortical regions. Changes in motor map have been associated with plastic changes of the human motor system7. Recent advancements in robotic TMS technology have brought new opportunities to improve motor mapping efficiency and accuracy. Our group has recently demonstrated that robotic TMS motor mapping is feasible, efficient, and well tolerated in children8.
Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that can shift cortical excitability and modulate human behaviors. There has been a multitude of studies examining the effect of tDCS in adults (&#62;10,000 subjects) but less than 2% of studies have focused on the developing brain9. Translation of adult evidence to pediatrics applications is complex, and modified protocols are needed due to complex differences in children. For example, we and others have shown that children experience larger and stronger electric fields compared to adults10,11. Standardization of tDCS methods in children is important to ensure safe and consistent application, improve replication, and advance the field. Experience of motor learning modulation tDCS in children is limited but increasing12. Translational applications of tDCS to specific cerebral palsy populations are advancing towards late phase clinical trials13. Efforts toward more focal stimulation applied through high-definition tDCS (HD-tDCS) has only just been studied for the first time in children14. We demonstrated that HD-tDCS produces similar improvements in motor learning as conventional tDCS in healthy children14. Describing HD-tDCS methods will allow for replication and further applications of such protocols in children.

<table>
	<tbody>
		<tr>
			<td>1x1 SMARTscan Stimulator</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/1x1/tdcs/device</td>
			<td></td>
		</tr>
		<tr>
			<td>4x1 HD-tDCS Adaptor</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/hd-tdcs/4x1</td>
			<td></td>
		</tr>
		<tr>
			<td>Brainsight Neuronavigation</td>
			<td>Roge Resolution</td>
			<td>https://www.rogue-resolutions.com/catalogue/neuro-navigation/brainsight-tms-navigation/</td>
			<td></td>
		</tr>
		<tr>
			<td>Carbon Rubber Electrode</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/1x1/accessories/carbon-ruber-electrode</td>
			<td></td>
		</tr>
		<tr>
			<td>EASYpad Electrode</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/1x1/accessories/1x1-easypad</td>
			<td></td>
		</tr>
		<tr>
			<td>EASYstraps</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/1x1/accessories/1x1-easystrap</td>
			<td></td>
		</tr>
		<tr>
			<td>EMG Amplifier</td>
			<td>Bortec Biomedical</td>
			<td>http://www.bortec.ca/pages/amt_16.htm</td>
			<td></td>
		</tr>
		<tr>
			<td>HD1 Electrode Holder</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/hd-tdcs/accessories/hd1-holder</td>
			<td>Standard Base HD-Electrode Holder for High Definition tES (HD-tES)</td>
		</tr>
		<tr>
			<td>HD-Electrode</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/hd-tdcs/accessories/hd-electrode</td>
			<td>Sintered ring HD-Electrode.</td>
		</tr>
		<tr>
			<td>HD-Gel</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/hd-tdcs/accessories/hd-gel</td>
			<td>HD-GEL for High Definition tES (HD-tES)</td>
		</tr>
		<tr>
			<td>Micro 1401 Data Acquisition System</td>
			<td>Cambridge Electronics http://ced.co.uk/products/mic3in</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Purdue Pegboard</td>
			<td>Lafayette Instrument Company</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Saline solution</td>
			<td>Baxter</td>
			<td>http://www.baxter.ca/en/products-expertise/iv-solutions-premixed-drugs/products/iv-solutions.page</td>
			<td></td>
		</tr>
		<tr>
			<td>Soterix Medical HD-Cap</td>
			<td>Soterix Medical Inc.</td>
			<td>https://soterixmedical.com/research/hd-tdcs/accessories/hd-cap</td>
			<td></td>
		</tr>
		<tr>
			<td>TMS Robot</td>
			<td>Axilium Robotics</td>
			<td>http://www.axilumrobotics.com/en/</td>
			<td></td>
		</tr>
		<tr>
			<td>TMS Stimulator and Coil</td>
			<td>Magstim Inc</td>
			<td>https://www.magstim.com/neuromodulation/</td>
			<td></td>
		</tr>
	</tbody>
</table>

non-invasive modulation and robotic mapping of motor cortex in the developing brain

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries unique challenges in children. Similarly, transcranial direct current stimulation (tDCS) can improve motor learning in adults but has only recently been applied to children. The use of tDCS and emerging techniques like high&#8211;definition tDCS (HD-tDCS) require special methodological considerations in the developing brain. Robotic TMS motor mapping may confer unique advantages for mapping, particularly in the developing brain. Here, we aim to provide a practical, standardized approach for two integrated methods capable of simultaneously exploring motor cortex modulation and motor maps in children. First, we describe a protocol for robotic TMS motor mapping. Individualized, MRI-navigated 12x12 grids centered on the motor cortex guide a robot to administer single-pulse TMS. Mean motor evoked potential (MEP) amplitudes per grid point are used to generate 3D motor maps of individual hand muscles with outcomes including map area, volume, and center of gravity. Tools to measure safety and tolerability of both methods are also included. Second, we describe the application of both tDCS and HD-tDCS to modulate the motor cortex and motor learning. An experimental training paradigm and sample results are described. These methods will advance the application of non-invasive brain stimulation in children.

Using the methods presented here, we completed a randomized, sham-controlled interventional trial8. Right-handed children (n = 24, ages 12-18) with no contraindications for both types of non-invasive brain stimulation were recruited. Participants were specifically excluded in this study if on neuropsychotropic medication or if they were not na&#239;ve to tDCS. There were no dropouts.
Robotic TMS motor map...

Watch this Scientific Journal Video about Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain at JoVE.com

Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain

We demonstrate protocols for the modulation (tDCS, HD-tDCS) and mapping (robotic TMS) of the motor cortex in children.

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries ...

non-invasive-modulation-robotic-mapping-motor-cortex-developing

Research

JoVE Journal

Neuroscience

6.7K Views.  University of Calgary. We demonstrate protocols for the modulation (tDCS, HD-tDCS) and mapping (robotic TMS) of the motor cortex in children.

Video: Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain

Functional Imaging of Auditory Cortex in Adult Cats using High-field fMRI

Current knowledge of sensory processing in the mammalian auditory system is mainly derived from electrophysiological studies in a variety of animal models, including monkeys, ferrets, bats, rodents, and cats. In order to draw suitable parallels between human and animal models of auditory function, it is important to establish a bridge between human functional imaging studies and animal electrophysiological studies. Functional magnetic resonance imaging (fMRI) is an established, minimally invasive method of measuring broad patterns of hemodynamic activity across different regions of the cerebral cortex. This technique is widely used to probe sensory function in the human brain, is a useful tool in linking studies of auditory processing in both humans and animals and has been successfully used to investigate auditory function in monkeys and rodents. The following protocol describes an experimental procedure for investigating auditory function in anesthetized adult cats by measuring stimulus-evoked hemodynamic changes in auditory cortex using fMRI. This method facilitates comparison of the hemodynamic responses across different models of auditory function thus leading to a better understanding of species-independent features of the mammalian auditory cortex.

Functional studies of the auditory system in mammals have traditionally been conducted using spatially-focused techniques such as electrophysiological recordings. The following protocol describes a method of visualizing large-scale patterns of evoked hemodynamic activity in the cat auditory cortex using functional magnetic resonance imaging.

Current knowledge of sensory processing in the mammalian auditory system is mainly derived from electrophysiological studies in a variety of animal ...

Live Imaging of Mitosis in the Developing Mouse Embryonic Cortex

Although of short duration, mitosis is a complex and dynamic multi-step process fundamental for development of organs including the brain. In the developing cerebral cortex, abnormal mitosis of neural progenitors can cause defects in brain size and function. Hence, there is a critical need for tools to understand the mechanisms of neural progenitor mitosis. Cortical development in rodents is an outstanding model for studying this process. Neural progenitor mitosis is commonly examined in fixed brain sections. This protocol will describe in detail an approach for live imaging of mitosis in ex vivo embryonic brain slices. We will describe the critical steps for this procedure, which include: brain extraction, brain embedding, vibratome sectioning of brain slices, staining and culturing of slices, and time-lapse imaging. We will then demonstrate and describe in detail how to perform post-acquisition analysis of mitosis. We include representative results from this assay using the vital dye Syto11, transgenic mice (histone H2B-EGFP and centrin-EGFP), and in utero electroporation (mCherry-&#945;-tubulin). We will discuss how this procedure can be best optimized and how it can be modified for study of genetic regulation of mitosis. Live imaging of mitosis in brain slices is a flexible approach to assess the impact of age, anatomy, and genetic perturbation in a controlled environment, and to generate a large amount of data with high temporal and spatial resolution. Hence this protocol will complement existing tools for analysis of neural progenitor mitosis.

Neural progenitor mitosis is a critical parameter of neurogenesis. Much of our understanding of neural progenitor mitosis is based on analysis of fixed tissue. Live imaging in embryonic brain slices is a versatile technique to assess mitosis with high temporal and spatial resolution in a controlled environment.

Although of short duration, mitosis is a complex and dynamic multi-step process fundamental for development of organs including the brain. In the ...

Non-invasive Parenchymal, Vascular and Metabolic High-frequency Ultrasound and Photoacoustic Rat Deep Brain Imaging

Photoacoustics and high frequency ultrasound stands out as powerful tools for neurobiological applications enabling high-resolution imaging on the central nervous system of small animals. However, transdermal and transcranial neuroimaging is frequently affected by low sensitivity, image aberrations and loss of space resolution, requiring scalp or even skull removal before imaging. To overcome this challenge, a new protocol is presented to gain significant insights in brain hemodynamics by photoacoustic and high-frequency ultrasounds imaging with the animal skin and skull intact. The procedure relies on the passage of ultrasound (US) waves and laser directly through the fissures that are naturally present on the animal cranium. By juxtaposing the imaging transducer device exactly in correspondence to these selected areas where the skull has a reduced thickness or is totally absent, one can acquire high quality deep images and explore internal brain regions that are usually difficult to anatomically or functionally describe without an invasive approach. By applying this experimental procedure, significant data can be collected in both sonic and optoacoustic modalities, enabling to image the parenchymal and the vascular anatomy far below the head surface. Deep brain features such as parenchymal convolutions and fissures separating the lobes were clearly visible. Moreover, the configuration of large and small blood vessels was imaged at several millimeters of depth, and precise information were collected about blood fluxes, vascular stream velocities and the hemoglobin chemical state. This repertoire of data could be crucial in several research contests, ranging from brain vascular disease studies to experimental techniques involving the systemic administration of exogenous chemicals or other objects endowed with imaging contrast enhancement properties. In conclusion, thanks to the presented protocol, the US and PA techniques become an attractive noninvasive performance-competitive means for cortical and internal brain imaging, retaining a significant potential in many neurologic fields.

The present work describes a new protocol to perform non-invasive high-frequency ultrasound and photoacoustic based imaging on rat brain, to efficiently visualize deep subcortical regions and their vascular patterns by directing signals on skull foramina naturally present on animal cranium.

Photoacoustics and high frequency ultrasound stands out as powerful tools for neurobiological applications enabling high-resolution imaging on the central ...

Non-invasive Assessment of Changes in Corticomotoneuronal Transmission in Humans

The corticospinal pathway is the major pathway connecting the brain with the muscles and is therefore highly relevant for movement control and motor learning. There exists a number of noninvasive electrophysiological methods investigating the excitability and plasticity of this pathway. However, most methods are based on quantification of compound potentials and neglect that the corticospinal pathway consists of many different connections that are more or less direct. Here, we present a method that allows testing excitability of different fractions of the corticospinal transmission. This so called H-reflex conditioning technique allows one to assess excitability of the fastest (monosynaptic) and also polysynaptic corticospinal pathways. Furthermore, by using two different stimulation sites, the motor cortex and the cervicomedullary junction, it allows not only differentiation between cortical and spinal effects but also assessment of transmission at the corticomotoneural synapse. In this manuscript, we describe how this method can be used to assess corticomotoneural transmission after low-frequency repetitive transcranial magnetic stimulation, a method that was previously shown to reduce excitability of cortical cells. Here we demonstrate that not only cortical cells are affected by this repetitive stimulation but also transmission at the corticomotoneuronal synapse at the spinal level. This finding is important for the understanding of basic mechanisms and sites of neuroplasticity. Besides investigation of basic mechanisms, the H-reflex conditioning technique may be applied to test changes in corticospinal transmission following behavioral (e.g., training) or therapeutic interventions, pathology or aging and therefore allows a better understanding of neural processes that underlie movement control and motor learning.

The aim of the present study was to assess changes in transmission at the corticomotoneuronal synapses in humans after repetitive transcranial magnetic stimulation. For this purpose, an electrophysiological method is introduced that allows assessment of pathway specific corticospinal transmission, i.e. differentiation of fast, direct corticospinal pathways from polysynaptic connections.

The corticospinal pathway is the major pathway connecting the brain with the muscles and is therefore highly relevant for movement control and motor ...

Effects of Transcranial Alternating Current Stimulation on the Primary Motor Cortex by Online Combined Approach with Transcranial Magnetic Stimulation

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific frequency and in turn modulate ongoing cortical oscillatory activity. This neurotool allows the establishment of a causal link between endogenous oscillatory activity and behavior. Most of the tACS studies have shown online effects of tACS. However, little is known about the underlying action mechanisms of this technique because of the AC-induced artifacts on Electroencephalography (EEG) signals. Here we show a unique approach to investigate online physiological frequency-specific effects of tACS of the primary motor cortex (M1) by using single pulse Transcranial Magnetic Stimulation (TMS) to probe cortical excitability changes. In our setup, the TMS coil is placed over the tACS electrode while Motor Evoked Potentials (MEPs) are collected to test the effects of the ongoing M1-tACS. So far, this approach has mainly been used to study the visual and motor systems. However, the current tACS-TMS setup can pave the way for future investigations of cognitive functions. Therefore, we provide a step-by-step manual and video guidelines for the procedure.

Transcranial Alternating Current Stimulation (tACS) allows the modulation of cortical excitability in a frequency-specific fashion. Here we show a unique approach which combines online tACS with single pulse Transcranial Magnetic Stimulation (TMS) in order to "probe" cortical excitability by means of Motor Evoked Potentials.

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific ...

Imaging Neural Activity in the Primary Somatosensory Cortex Using Thy1-GCaMP6s Transgenic Mice

The mammalian brain exhibits marked symmetry across the sagittal plane. However, detailed description of neural dynamics in symmetric brain regions in adult mammalian animals remains elusive. In this study, we describe an experimental procedure for measuring calcium dynamics through dual optical windows above bilateral primary somatosensory corticies (S1) in Thy1-GCaMP6s transgenic mice using 2-photon (2P) microscopy. This method enables recordings and quantifications of neural activity in bilateral mouse brain regions one at a time in the same experiment for a prolonged period in vivo. Key aspects of this method, which can be completed within an hour, include minimally invasive surgery procedures for creating dual optical windows, and the use of 2P imaging. Although we only demonstrate the technique in the S1 area, the method can be applied to other regions of the living brain facilitating the elucidation of structural and functional complexities of brain neural networks.

Imaging Neural Activity in the Primary Somatosensory Cortex Using Thy1-GCaMP6s Transgenic Mice

We describe an experimental procedure for measuring neuronal activity through dual optical windows above bilateral primary somatosensory corticies (S1) in Thy1-GCaMP6s transgenic mice using 2-photon (2P) microscopy in vivo.

The mammalian brain exhibits marked symmetry across the sagittal plane. However, detailed description of neural dynamics in symmetric brain regions in ...

In Vivo Single-Molecule Tracking at the Drosophila Presynaptic Motor Nerve Terminal

An increasing number of super-resolution microscopy techniques are helping to uncover the mechanisms that govern the nanoscale cellular world. Single-molecule imaging is gaining momentum as it provides exceptional access to the visualization of individual molecules in living cells. Here, we describe a technique that we developed to perform single-particle tracking photo-activated localization microscopy (sptPALM) in Drosophila larvae. Synaptic communication relies on key presynaptic proteins that act by docking, priming, and promoting the fusion of neurotransmitter-containing vesicles with the plasma membrane. A range of protein-protein and protein-lipid interactions tightly regulates these processes and the presynaptic proteins therefore exhibit changes in mobility associated with each of these key events. Investigating how mobility of these proteins correlates with their physiological function in an intact live animal is essential to understanding their precise mechanism of action. Extracting protein mobility with high resolution in vivo requires overcoming limitations such as optical transparency, accessibility, and penetration depth. We describe how photoconvertible fluorescent proteins tagged to the presynaptic protein Syntaxin-1A can be visualized via slight oblique illumination and tracked at the motor nerve terminal or along the motor neuron axon of the third instar Drosophila larva.

In Vivo Single-Molecule Tracking at the Drosophila Presynaptic Motor Nerve Terminal

Here we illustrate how single molecule photo-activated localization microscopy can be carried out on the motor nerve terminal of a live Drosophila melanogaster third instar larva.

An increasing number of super-resolution microscopy techniques are helping to uncover the mechanisms that govern the nanoscale cellular world. ...

Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic field pulses. The initiation of cortical activation or its modulation depends on the background activation of the neurons of the cortical region activated, the characteristics of the coil, its position and its orientation with respect to the head. TMS combined with simultaneous electrocephalography (EEG) and neuronavigation (nTMS-EEG) allows for the assessment of cortico-cortical excitability and connectivity in almost all cortical areas in a reproducible manner. This advance makes nTMS-EEG a powerful tool that can accurately assess brain dynamics and neurophysiology in test-retest paradigms that are required for clinical trials. Limitations of this method include artifacts that cover the initial brain reactivity to stimulation. Thus, the process of removing artifacts may also extract valuable information. Moreover, the optimal parameters for dorsolateral prefrontal (DLPFC) stimulation are not fully known and current protocols utilize variations from the motor cortex (M1) stimulation paradigms. However, evolving nTMS-EEG designs hope to address these issues. The protocol presented here introduces some standard practices for assessing neurophysiological functioning from stimulation to the DLPFC that can be applied in patients with treatment resistant psychiatric disorders that receive treatment such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST) or electroconvulsive therapy (ECT).

The protocol presented here is for TMS-EEG studies utilizing intracortical excitability test-retest design paradigms. The intent of the protocol is to produce reliable and reproducible cortical excitability measures for assessing neurophysiological functioning related to therapeutic interventions in the treatment of neuropsychiatric diseases such as major depression.

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic ...

Evaluation of Hemisphere Lateralization with Bilateral Local Field Potential Recording in Secondary Motor Cortex of Mice

This article demonstrates complete, detailed procedures for both in vivo bilateral recording and analysis of local field potential (LFP) in the cortical areas of mice, which are useful for evaluating possible laterality deficits, as well as for assessing brain connectivity and coupling of neural network activities in rodents. The pathological mechanisms underlying Alzheimer&#39;s disease (AD), a common neurodegenerative disease, remain largely unknown. Altered brain laterality has been demonstrated in aging people, but whether or not abnormal lateralization is one of the early signs of AD has not been determined. To investigate this, we recorded bilateral LFPs in 3-5-month-old AD model mice, APP/PS1, together with littermate wild type (WT) controls. The LFPs of the left and right secondary motor cortex (M2), specifically in the gamma band, were more synchronized in APP/PS1 mice than in WT controls, suggesting a declined hemispheric asymmetry of bilateral M2 in this AD mouse model. Notably, the recording and data analysis processes are flexible and easy to carry out, and can also be applied to other brain pathways when conducting experiments that focus on neuronal circuits.

We present in vivo electrophysiological recording of the local field potential (LFP) in bilateral secondary motor cortex (M2) of mice, which can be applied to evaluate hemisphere lateralization. The study revealed altered levels of synchronization between the left and right M2 in APP/PS1 mice compared to WT controls.

This article demonstrates complete, detailed procedures for both in vivo bilateral recording and analysis of local field potential (LFP) in the cortical ...

Translational Brain Mapping at the University of Rochester Medical Center: Preserving the Mind Through Personalized Brain Mapping

The Translational Brain Mapping Program at the University of Rochester is an interdisciplinary effort that integrates cognitive science, neurophysiology, neuroanesthesia, and neurosurgery. Patients who have tumors or epileptogenic tissue in eloquent brain areas are studied preoperatively with functional and structural MRI, and intraoperatively with direct electrical stimulation mapping. Post-operative neural and cognitive outcome measures fuel basic science studies about the factors that mediate good versus poor outcome after surgery, and how brain mapping can be further optimized to ensure the best outcome for future patients. In this article, we describe the interdisciplinary workflow that allows our team to meet the synergistic goals of optimizing patient outcome and advancing scientific understanding of the human brain.

This article provides an overview of a multi-modal brain mapping program designed to identify regions of the brain that support critical cognitive functions in individual neurosurgery patients.

The Translational Brain Mapping Program at the University of Rochester is an interdisciplinary effort that integrates cognitive science, neurophysiology, ...