Supported by the 2014-2015 Neurosurgery Research and Education Foundation (NREF) award and a 2014 Grant-In-Aid Award from Louisiana State University Shreveport School of Medicine (J.A.W.). We thank S. Harold and C.M. Keller for their invaluable technical assistance and teaching.

<ol>
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N., Hamani, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Augmentative+therapies+do+not+potentiate+the+antidepressant-like+effects+of+deep+brain+stimulation+in+rats.">Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats.</a> J Affect Disord. 161, 87-90 (2014).</li><li>Pascoli, V., Turiault, M., Luscher, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reversal+of+cocaine-evoked+synaptic+potentiation+resets+drug-induced+adaptive+behaviour.">Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour.</a> Nature. 481, 71-75 (2012).</li><li>Gazit, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Programmed+deep+brain+stimulation+synchronizes+VTA+gamma+band+field+potential+and+alleviates+depressive-like+behavior+in+rats.">Programmed deep brain stimulation synchronizes VTA gamma band field potential and alleviates depressive-like behavior in rats.</a> Neuropharmacology. 91, 135-141 (2015).</li><li>Mayberg, H. 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The authors have no competing financial interests with regards to this methodology.

Although the exact mechanisms of deep brain stimulation are not fully characterized, DBS efficacy for both motor and psychiatric disorders may result from a dynamic interaction between the electrical therapy and the functioning of various subcortical and cortical brain regions over time6,22-26. While non-contingent methods of methamphetamine delivery to rodents are well-described27,28, these methods are most appropriate for discrete investigations of drug pharmacokinetics and neurochemical effects27-29. Operant IV drug self-administration, by incorporating an element of motivation for drug, is ideally suited for the study of how electrical therapies like DBS interact with pathological behaviors over time. The procedures we describe examine the effects of DBS in one environment on contingent methamphetamine use in a different environment.
There are three key steps in our IV methamphetamine self-administration paradigm: 1) Induction of rapid acquisition and escalation of drug intake during long access sessions, 2) Maintenance of a stable, high rate of drug intake during subsequent short access sessions and 3) Development of a front loading pattern of drug taking. This paradigm can be accomplished in a 2 to 3 week timeframe with 10 - 12 rats per experiment, which is both cost-effective and ideally suited to test the effects of DBS given the potentially limited lifespan of head caps in rodents using psycho-stimulants. This procedure, like other paradigms that incorporate a period of long access19,30,31 reasonably simulates some aspects of substance use disorders; it demonstrates both escalation of use and high motivation to obtain drug with early session &#8220;drug-loading,&#8221; which are important aspects of human dependence versus recreational use19,30. Rodents who have long access exposure to IV methamphetamine also demonstrate cognitive deficits32, distinct responses to pharmacological treatment33, pharmacokinetics34 and neurochemical changes35 that are more similar to humans suffering from chronic methamphetamine use disorder than rodents with only short access exposure.
Likewise there are three key steps in our deep brain stimulation procedure: 1) Habituation to the DBS environment, including the head tether connection, for one or two &#8220;mock&#8221; sessions, 2) Daily, intermittent delivery of active stimulation using a commercial system, and 3) DBS disconnection and subsequent transport to the drug setting. This paradigm is designed to mimic the process of non-invasive therapies like TMS rather than that of traditional continuous DBS. Fully implanted, programmable DBS systems like those used for common movement disorders3 will be marginally feasible in patients suffering from psycho-stimulant dependence for several aforementioned reasons. Intermittent electrical treatment strategies that do not involve high-risk surgery and aftercare, like TMS, may be better adapted to this patient population. The methods we have described will allow investigators to develop and refine treatment strategies that can modify drug-related behavior while being delivered outside of the drug environment in a restricted timeframe. There is accumulating evidence that transient intracranial electrical stimulation that is patterned after specific neurophysiological deficits23 or combined with systemic pharmacotherapy36 exert long-lasting positive effects on psychiatric and drug-related behaviors for several weeks after the treatment has ceased.
The needs for initial excellent surgical technique and for ongoing care of multiple surgical sites during intense drug-use are the main limitations of this methodology. If either the IV catheter or the DBS electrodes become non-operational and/or infected, the rat must exit the study. Jugular catheter and intracranial electrode placements under strict sterile technique are best learned from experienced investigators prior to initiating these procedures independently.
This procedure is amenable to several modifications and future investigations, including examination of: 1) alternate stimulation parameters (e.g.,-stimulation waveform, pulse width, frequency, amplitude), 2) other potential therapeutic brain targets (e.g.,-nucleus accumbens core, medial prefrontal cortex, midbrain, habenula), 3) different DBS delivery patterns (e.g.,- daily DBS delivery, weekly DBS delivery, DBS at various intervals prior to operant sessions, DBS before acquisition), and, perhaps most exciting, 4) combinations of short-duration DBS and pharmaceutical agents that imitate optogenetic stimulation of selective pathways and exert enduring behavioral modifications36.

Methamphetamine is a psychostimulant that produces an intense and prolonged euphoria due to an acute increase in synaptic monoamines, particularly dopamine. Methamphetamine dependence is an epidemic health problem with an estimated 25 to 34 million users globally and no proven treatment1,2. There is a substantial need to develop novel therapeutic strategies for methamphetamine dependence. Deep brain stimulation (DBS) is a neurosurgical procedure that uses a brain &#8220;pacemaker&#8221; to normalize disruptive neuronal firing patterns that occur in certain diseases, including Parkinson&#8217;s disease, dystonia, and essential tremor3. Recent human case reports suggest that DBS may also be an effective treatment for alcohol and drug dependence, but preclinical evidence regarding psychostimulants (e.g., cocaine, methamphetamine) is limited4-8.
Continuous deep brain stimulation, as it is currently practiced, requires exceptional cooperation from the patient and his/her family. Meticulous wound care and personal hygiene are required to protect the underlying pacemaker hardware, which is susceptible to infection even in patients who are not using intravenous drugs with resultant bacteremia. Regular follow-up of the DBS device is also necessary given the open loop design of the system; experienced physicians alter the settings of modern DBS to decrease target symptoms during routine clinic appointments3. This treatment paradigm will be limited in cocaine and methamphetamine users due to their challenging psychosocial situations. Several rodent studies have imitated this impractical paradigm by examining DBS effects when the therapy is delivered continuously during cocaine self-administration procedures in the drug-use environment9-11.
Non-invasive discontinuous techniques that do not require indwelling hardware, like transcranial magnetic stimulation (TMS), may be a better option for treatment of substance use disorders12. TMS is delivered non-invasively using an external headcoil to generate electrical fields in a particular brain target during daily, intermittent treatments. The recent advent of H coil or &#8220;deep&#8221; TMS allows deeper brain structures to be stimulated, in addition to cortical sites, expanding its potential use13,14. Both therapies are delivered discontinuously during a series of sessions in a different environment than that of primary drug use and have shown promise in both human and rodent trials for drug dependence13,15-17. The window to treat methamphetamine dependent patients will likely be during periods of sobriety such as court-mandated rehabilitation, not during street binges when they can experience violent or erratic behavior18. As such, the aim of this article is to describe the delivery of electrical stimulation that is temporally and spatially separate from the drug-use environment, which more closely approximates what is possible in humans, for the treatment of IV methamphetamine dependence.

<table>
	<tbody>
		<tr>
			<td>Rodent operant chambers</td>
			<td>Med Associates, Inc</td>
			<td>ENV-008CT</td>
			<td>Med Associates Inc. PO Box 319 St. Albans, Vermont 05478 USA Phone: (802) 527-2343</td>
		</tr>
		<tr>
			<td>Kopf Small Animal Stereotaxic Instrument with Digital Display Console</td>
			<td>Kopf Instruments</td>
			<td>Model 940</td>
			<td>Kopf Phone: 1-877-352-3275 Fax: 1-818-352-3275 Email: sales@kopfinstruments.net</td>
		</tr>
		<tr>
			<td>Z-Series 3-DSP Bioamp Processor</td>
			<td>Tucker Davis Technologies</td>
			<td>RZ5D</td>
			<td>Tucker-Davis Technologies&#160;11930 Research Circle Alachua, FL 32615&#160;USA Ph: 386-462-9622&#160;www.tdt.com</td>
		</tr>
		<tr>
			<td>Z-Series 32-Channel Stimulator</td>
			<td>Tucker Davis Technologies</td>
			<td>IZ2-32</td>
			<td>Software is accompanied by a manual that discusses how to program experiments using the OpenEx platform, which can be accessed here: http://www.tdt.com/files/manuals/OpenEx_User_Guide.pdf</td>
		</tr>
		<tr>
			<td>48 Volt LI-ION Battery Pack for IZ2 Stimulator</td>
			<td>Tucker Davis Technologies</td>
			<td>LZ48-200</td>
			<td></td>
		</tr>
		<tr>
			<td>32-Channel Splitter Box for PZ5</td>
			<td>Tucker Davis Technologies</td>
			<td>S-BOX_PZ5</td>
			<td></td>
		</tr>
		<tr>
			<td>OpenEx Ext Software Package for Multi-Channel Neural Recording</td>
			<td>Tucker Davis Technologies</td>
			<td>OpenEx</td>
			<td></td>
		</tr>
		<tr>
			<td>Platinum-iridium stimulating electrodes</td>
			<td>Plastics One Inc</td>
			<td>MS303/8-B/SPC ELECT PT 2C TW .005&#34;</td>
			<td>Plastics One Inc P.O.Box 21465, S.W. Roanoke, VA 24018, PH 540-772-7950</td>
		</tr>
		<tr>
			<td>2-channel cables between stimulator and commutator</td>
			<td>Plastics One Inc</td>
			<td>305-441/2 W/ Spring</td>
			<td></td>
		</tr>
		<tr>
			<td>2-channel cables between commutator and electrode pedestal</td>
			<td>Plastics One Inc</td>
			<td>305-305 W/ Spring</td>
			<td></td>
		</tr>
		<tr>
			<td>4-channel commutators</td>
			<td>Plastics One Inc</td>
			<td>SL2+2C and SL2+SC/SB</td>
			<td></td>
		</tr>
	</tbody>
</table>

a general method for evaluating deep brain stimulation effects on intravenous methamphetamine self-administration

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people. There is a need for novel, effective and practical treatment strategies that are validated in animal models. Neuromodulation, including deep brain stimulation (DBS) therapy, refers to the use of electricity to influence pathological neuronal activity and has shown promise for psychiatric disorders, including drug dependence. DBS in clinical practice involves the continuous delivery of stimulation into brain structures using an implantable pacemaker-like system that is programmed externally by a physician to alleviate symptoms. This treatment will be limited in methamphetamine users due to challenging psychosocial situations. Electrical treatments that can be delivered intermittently, non-invasively and remotely from the drug-use setting will be more realistic. This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence. Methamphetamine dependence is rapidly developed in rodents using an operant paradigm of intravenous (IV) self-administration that incorporates a period of extended access to drug and demonstrates both escalation of use and high motivation to obtain drug.

Following placement of an IV jugular catheter and intracranial DBS electrodes, rodents can be successfully trained to self-administer IV methamphetamine after a brief recovery period. Figure 3 shows that rats will acquire and escalate methamphetamine self-administration after 2 days of extended-access to drug with an average of 168 &#177;&#160;12 infusions per session by day 4.
Rats are then moved to a daily 2-hr schedule of operant training for two reasons: 1) to prevent methamphetamine toxicity and severe behavioral alterations with persistent, prolonged access and 2) to establish a relatively stable rate of responding that can be manipulated by various therapeutic interventions. Figure 4 shows that the average number of total infusions per short access session over the second week is 75 &#177; 8 and generally varies by less than 10% day-to-day. Figure 5 demonstrates that rats develop an increased motivation to take drug as shown by the emergence of a &#8220;front-loading&#8221; pattern of intake by day 6 of training as compared to day 1. Once this develops, the effect is largely sustained over subsequent sessions (data not shown).
Figure 6 shows that bilateral DBS delivered in the non-drug environment resulted in a marked decrease of operant IV methamphetamine self-administration on three of five days compared to the sham stimulated group. The nucleus accumbens shell was targeted given its known involvement in drug-consummatory behavior8 using the following stereotactic coordinates relative to bregma (AP + 1.6, DV - 8.5, ML&#160;&#177;&#160;2.4). Stimulation parameters and duration were loosely based on previous published experience with DBS for the treatment of psychiatric disease8,20,21 but can be adjusted depending on the experimenter&#8217;s needs. Error bars are moderate and not all days reach significance indicating the range of responses that can be seen in behavioral assessments despite a clear treatment effect. Increasing the number of rats per experiment can help compensate for this natural variability. 11 animals were initially used for this experiment. One animal was euthanized for poor feeding post-operatively, one animal was excluded due to seizures, and one animal was excluded due to DBS electrode malfunction leaving us with a total of 8 animals (N = 4 Sham; N = 4 active DBS). In general starting with about 10 - 12 rats for each experiment will allow for its successful completion.
<img alt="Figure 1" src="/files/ftp_upload/53266/53266fig1.jpg" />
Figure 1. Visual Programming Language. The investigator uses a visual programming language, like the example shown here, to design a program that can deliver brain stimulation to multiple animals simultaneously at user-entered parameters. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" src="/files/ftp_upload/53266/53266fig2.jpg" />
Figure 2. Visual Control Panel. Prior to the start of the experiment, the investigator specifies the desired frequency, pulse width, and amplitude on the left side of a visual control panel. Here stimulation parameters are: current intensity 200 &#956;A; pulse width 61 msec; pulse frequency 130 Hz. Once stimulation is initiated, the waveform for the active current delivery is displayed on the right. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" src="/files/ftp_upload/53266/53266fig3.jpg" />
Figure 3. Acquisition of IV Methamphetamine Self-Administration. Total operant responding (360&#160;min) data were analyzed using a repeated-measures ANOVA with the daily session defined as the repeated measure. All analyses that were&#160;p&#160;&#60;0.05 were considered significant. Data is mean &#177; standard error. Total methamphetamine infusions during the daily 6-hr operant sessions over the first four days of operant training. + P &#60;0.05 compared to sessions 1 and 2. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" src="/files/ftp_upload/53266/53266fig4.jpg" />
Figure 4. Maintenance of IV Methamphetamine Self-Administration. Total operant responding (120&#160;min) data were analyzed using a repeated-measures ANOVA with the daily session defined as the repeated measure. All analyses that were&#160;p&#160;&#60;0.05 were considered significant. Data is mean &#177; standard error. Total methamphetamine infusions during the daily 2-hr operant sessions over the second week of operant training, demonstrating stable but intense drug-taking behavior. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" src="/files/ftp_upload/53266/53266fig5.jpg" />
Figure 5. Development of Motivation to Take Drug. Operant responding was totaled every 15 min for the first hour and data were analyzed using a repeated-measures ANOVA with each 15-min quadrant defined as the repeated measure. All analyses that were&#160;p&#160;&#60;0.05 were considered significant. Data is mean &#177;&#160;standard error. A &#8220;front-loading&#8221; pattern is not present on day 1 of operant training but develops by the second week, indicating a strong motivation to take drug. + P &#60;0.05 compared to 30, 45, and 60 min, ++ P &#60;0.05 compared to 45 and 60 min, +++ P &#60;0.05 compared to 60 min. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" src="/files/ftp_upload/53266/53266fig6.jpg" />
Figure 6. DBS Effects on IV Methamphetamine Self-Administration. Total operant responding in the first hour (60&#160;min) data were analyzed using a mixed ANOVA with a between subject variable of treatment (DBS vs Sham) and a repeated measure of daily session. All analyses that were&#160;p &#60;0.05 were considered significant. Data is mean &#177; standard error. Bilateral pre-operant deep brain stimulation significantly reduced the number of methamphetamine infusions over the first 60 min of operant responding on treatment days 3, 4, and 7. + P &#60;0.05 compared to sham group and baseline responding. Responding returned to baseline levels after daily treatment ended. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence.

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people.  There is a need ...

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15.1K Views.  Louisiana State University. This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence.

Video: A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

A Novel Procedure for Evaluating the Reinforcing Properties of Tastants in Laboratory Rats: Operant Intraoral Self-administration

This paper describes a novel method for studying the bio-behavioral basis of addiction to food. This method combines the surgical component of taste reactivity with the behavioral aspects of operant self-administration of drugs. Under very brief general anaesthesia, rats are implanted with an intraoral (IO) cannula that allows delivery of test solutions directly in the oral cavity. Animals are then tested in operant self-administration chambers whereby they can press a lever to receive IO infusions of test solutions. IO self-administration has several advantages over experimental procedures that involve drinking a solution from a spout&#160;or operant responding for solid pellets or solutions delivered in a receptacle. Here, we show that IO self-administration can be employed to study self-administration of high fructose corn syrup (HFCS). Rats were first tested for self-administration on a progressive ratio (PR) schedule, which assesses the maximum amount of operant behavior that will be emitted for different concentrations of HFCS (i.e.&#160;8%, 25%, and 50%). Following this test, rats self-administered these concentrations on a continuous schedule of reinforcement (i.e.&#160;one infusion for each lever press) for 10 consecutive days (1 session/day; each lasting 3 hr), and then they were retested on the PR schedule. On the continuous reinforcement schedule, rats took fewer infusions of higher concentrations, although the lowest concentration of HFCS (8%) maintained more variable self-administration. Furthermore, the PR tests revealed that 8% had lower reinforcing value than 25% and 50%. These results indicate that IO self-administration can be employed to study acquisition and maintenance of responding for sweet solutions. The sensitivity of the operant response to differences in concentration and schedule of reinforcement makes IO self-administration an ideal procedure to investigate the neurobiology of voluntary intake of sweets.

The current study evaluates a novel procedure for assessing the reinforcing effects of palatable solutions in laboratory rats: intraoral self-administration. To this end, operant responding (i.e.&#160;lever pressing) for intraoral infusions of sweet solutions at different concentrations was measured on continuous and progressive ratios schedules of reinforcement.

This paper describes a novel method for studying the bio-behavioral basis of addiction to food. This method combines the surgical component of taste ...

Transcranial Magnetic Stimulation for Investigating Causal Brain-behavioral Relationships and their Time Course

Transcranial magnetic stimulation (TMS) is a safe, non-invasive brain stimulation technique that uses a strong electromagnet in order to temporarily disrupt information processing in a brain region, generating a short-lived &#8220;virtual lesion.&#8221; Stimulation that interferes with task performance indicates that the affected brain region is necessary to perform the task normally. In other words, unlike neuroimaging methods such as functional magnetic resonance imaging (fMRI) that indicate correlations between brain and behavior, TMS can be used to demonstrate causal brain-behavior relations. Furthermore, by varying the duration and onset of the virtual lesion, TMS can also reveal the time course of normal processing. As a result, TMS has become an important tool in cognitive neuroscience. Advantages of the technique over lesion-deficit studies include better spatial-temporal precision of the disruption effect, the ability to use participants as their own control subjects, and the accessibility of participants. Limitations include concurrent auditory and somatosensory stimulation that may influence task performance, limited access to structures more than a few centimeters from the surface of the scalp, and the relatively large space of free parameters that need to be optimized in order for the experiment to work. Experimental designs that give careful consideration to appropriate control conditions help to address these concerns. This article illustrates these issues with TMS results that investigate the spatial and temporal contributions of the left supramarginal gyrus (SMG) to reading.

Transcranial magnetic stimulation (TMS) is a technique for non-invasively disrupting neural information processing and measuring its effect on behavior. When TMS interferes with a task, it indicates that the stimulated brain region is necessary for normal task performance, allowing one to systematically relate brain regions to cognitive functions.

Transcranial magnetic stimulation (TMS) is a safe, non-invasive brain stimulation technique that uses a strong electromagnet in order to temporarily ...

Combined Shuttle-Box Training with Electrophysiological Cortex Recording and Stimulation as a Tool to Study Perception and Learning

Shuttle-box avoidance learning is a well-established method in behavioral neuroscience and experimental setups were traditionally custom-made; the necessary equipment is now available by several commercial companies. This protocol provides a detailed description of a two-way shuttle-box avoidance learning paradigm in rodents (here Mongolian gerbils; Meriones unguiculatus) in combination with site-specific electrical intracortical microstimulation (ICMS) and simultaneous chronical electrophysiological in vivo recordings. The detailed protocol is applicable to study multiple aspects of learning behavior and perception in different rodent species.
Site-specific ICMS of auditory cortical circuits as conditioned stimuli here is used as a tool to test the perceptual relevance of specific afferent, efferent and intracortical connections. Distinct activation patterns can be evoked by using different stimulation electrode arrays for local, layer-dependent ICMS or distant ICMS sites. Utilizing behavioral signal detection analysis it can be determined which stimulation strategy is most effective for eliciting a behaviorally detectable and salient signal. Further, parallel multichannel-recordings using different electrode designs (surface electrodes, depth electrodes, etc.) allow for investigating neuronal observables over the time course of such learning processes. It will be discussed how changes of the behavioral design can increase the cognitive complexity (e.g. detection, discrimination, reversal learning).

Shuttle-box avoidance learning is well-established in behavioral neuroscience. This protocol describes how shuttle-box learning in rodents can be combined with site-specific electrical intracortical microstimulation (ICMS) and simultaneous chronical in vivo recordings as a tool to study multiple aspects of learning and perception.

Shuttle-box avoidance learning is a well-established method in behavioral neuroscience and experimental setups were traditionally custom-made; the ...

Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been maintaining the behavior. There is close correspondence between fear and human anxiety, and therefore studies of extinction learning might provide insight into the biological nature of anxiety-related disorders such as post-traumatic stress disorder, and they might help to develop strategies to treat them. Preclinical research aims to aid extinction learning and to induce targeted plasticity in extinction circuits to consolidate the newly formed memory. Vagus nerve stimulation (VNS) is a powerful approach that provides tight temporal and circuit-specific release of neurotransmitters, resulting in modulation of neuronal networks engaged in an ongoing task. VNS enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here, we provide a detailed protocol for the preparation of custom-made parts and the surgical procedures required for VNS in rats. Using this protocol we show how VNS can facilitate the extinction of conditioned fear responses in an auditory fear conditioning task. In addition, we provide evidence that VNS modulates synaptic plasticity in the pathway between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA), which is involved in the expression and modulation of extinction memory.

Vagus nerve stimulation (VNS) has emerged as a tool to induce targeted synaptic plasticity in the forebrain to modify a range of behaviors. This protocol describes how to implement VNS to facilitate the consolidation of fear extinction memory.

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been ...

A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training

Operant oral self-administration methods are commonly used to study the reinforcing properties of ethanol in animals. However, the standard methods require saccharin/sucrose fading, water deprivation and/or extended training to initiate operant responding in rats. This paper describes a novel and efficient method to quickly initiate operant responding for ethanol that is convenient for experimenters and does not require water deprivation or saccharin/sucrose fading, thus eliminating the potential confound of using sweeteners in ethanol operant self-administration studies. With this method, Wistar rats typically acquire and maintain self-administration of a 20% ethanol solution in less than two weeks of training. Furthermore, blood ethanol concentrations and rewards are positively correlated for a 30 min self-administration session. Moreover, naltrexone, an FDA-approved medication for alcohol dependence that has been shown to suppress ethanol self-administration in rodents, dose-dependently decreases alcohol intake and motivation to consume alcohol for rats self-administering 20% ethanol, thus validating the use of this new method to study the reinforcing properties of alcohol in rats.

This protocol describes a novel and efficient method to quickly initiate operant responding for ethanol in rats that, contrary to standard methods, does not require water deprivation or saccharin/sucrose fading to initiate responding.

Operant oral self-administration methods are commonly used to study the reinforcing properties of ethanol in animals. However, the standard methods ...

A Novel Approach to Assess Motor Outcome of Deep Brain Stimulation Effects in the Hemiparkinsonian Rat: Staircase and Cylinder Test

Deep brain stimulation of the subthalamic nucleus is an effective treatment option for Parkinson&#39;s disease. In our lab we established a protocol to screen different neurostimulation patterns in hemiparkinsonian (unilateral lesioned) rats. It consists of creating a unilateral Parkinson&#39;s lesion by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, implanting chronic stimulation electrodes into the subthalamic nucleus and evaluating motor outcomes at the end of 24 hr periods of cable-bound external neurostimulation. The stimulation was conducted with constant current stimulation. The amplitude was set 20% below the individual threshold for side effects. The motor outcome evaluation was done by the assessment of spontaneous paw use in the cylinder test according to Shallert and by the assessment of skilled reaching in the staircase test according to Montoya. This protocol describes in detail the training in the staircase box, the cylinder test, as well as the use of both in hemiparkinsonian rats. The use of both tests is necessary, because the staircase test seems to be more sensitive for fine motor skill impairment and exhibits greater sensitivity to change during neurostimulation. The combination of the unilateral Parkinson model and the two behavioral tests allows the assessment of different stimulation parameters in a standardized way.

Deep brain stimulation (DBS) is an effective treatment option for Parkinson's disease. We established a study design to screen novel stimulation paradigms in rats. The protocol describes the use of the staircase test and cylinder test for motor outcome assessment in DBS treated hemiparkinsonian rats.

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Visualization Method for Proprioceptive Drift on a 2D Plane Using Support Vector Machine

Proprioceptive drift, which is a perceptual shift in body-part position from the unseen real body to a visible body-like image, has been measured as the behavioral correlate for the sense of ownership. Previously, the estimation of proprioceptive drift was limited to one spatial dimension, such as height, width, or depth. As the hand can move freely in 3D, measuring proprioceptive drift in only one dimension is not sufficient for the estimation of the drift in real life situations. In this article, we provide a novel method to estimate proprioceptive drift on a 2D plane using the mirror illusion by combining an objective behavioral measurement (hand position tracking) and subjective, phenomenological assessment (subjective assessment of hand position and questionnaire) with a sophisticated machine learning approach. This technique permits not only an investigation of the underlying mechanisms of the sense of ownership and agency but also assists in the rehabilitation of a missing or paralyzed limb and in the design rules of real-time control systems with a self-body-like usability, in which the operator controls the system as if it were part of his/her own body.

This article describes a novel method to estimate proprioceptive drift on a 2D plane using the mirror illusion and combining a psychophysical procedure with an analysis using machine learning.

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How to Use the H1 Deep Transcranial Magnetic Stimulation Coil for Conditions Other than Depression

Deep transcranial magnetic stimulation (dTMS) is a relatively new technique that uses different coils for the treatment of different neuropathologies. The coils are made of soft copper windings in multiple planes that lie adjacent to the skull. They are located within a special helmet so that their magnetic fields combine and improve depth penetration. The H1 dTMS coil is designed to stimulate bilateral prefrontal cortices with greater effective stimulation over the left than the right. By positioning the left side of the coil close to the left dorsolateral prefrontal cortex (DLPFC), the H1 coil was used in a multisite study, leading to FDA approval for treatment-resistant depression. In this same position, the H1 coil was also explored as a possible treatment for negative symptoms of schizophrenia, bipolar depression, and migraine. When moved to different positions over the subject's skull, the H1 coil was also explored as a possible treatment for other conditions. Such manipulation of the H1 coil was demonstrated for PTSD and alcohol dependence by positioning it over the medial prefrontal cortex (mPFC), for anxiety by positioning it over the right prefrontal cortex (rPFC), for auditory hallucinations and tinnitus by positioning it over the temporoparietal junction (TPJ), and for Parkinson's and fatigue from multiple sclerosis (MS) by positioning it over the motor cortex (MC) and PFC. Corresponding electrical field diagrams measured with an oscilloscope through a saline-filled head are included.

The H1 deep transcranial magnetic stimulation coil is FDA-cleared for the treatment of depression. We demonstrate how to utilize the H1 for other conditions, such as auditory hallucinations and PTSD, by moving the helmet to different locations over the subject's skull.

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A Within-subjects Experimental Protocol to Assess the Effects of Social Input on Infant EEG

Despite the importance of social interactions for infant brain development, little research has assessed functional neural activation while infants socially interact. Electroencephalography (EEG) power is an advantageous technique to assess infant functional neural activation. However, many studies record infant EEG only during one baseline condition. This protocol describes a paradigm that is designed to comprehensively assess infant EEG activity in both social and nonsocial contexts as well as tease apart how different types of social inputs differentially relate to infant EEG. The within-subjects paradigm includes four controlled conditions. In the nonsocial condition, infants view objects on computer screens. The joint attention condition involves an experimenter directing the infant's attention to pictures. The joint attention condition includes three types of social input: language, face-to-face interaction, and the presence of joint attention. Differences in infant EEG between the nonsocial and joint attention conditions could be due to any of these three types of input. Therefore, two additional conditions (one with language input while the experimenter is hidden behind a screen and one with face-to-face interaction) were included to assess the driving contextual factors in patterns of infant neural activation. Representative results demonstrate that infant EEG power varied by condition, both overall and differentially by brain region, supporting the functional nature of infant EEG power. This technique is advantageous in that it includes conditions that are clearly social or nonsocial and allows for examination of how specific types of social input relate to EEG power. This paradigm can be used to assess how individual differences in age, affect, socioeconomic status, and parent-infant interaction quality relate to the development of the social brain. Based on the demonstrated functional nature of infant EEG power, future studies should consider the role of EEG recording context and design conditions that are clearly social or nonsocial.

This novel protocol is designed to assess the neural bases of social interaction in infants. The paradigm is designed to tease apart how various social inputs such as language, joint attention, and face-to-face interaction relate to infant neural activation. Infant EEG power is recorded during both social and nonsocial conditions.

Despite the importance of social interactions for infant brain development, little research has assessed functional neural activation while infants ...

Simultaneous Transcranial Alternating Current Stimulation and Functional Magnetic Resonance Imaging

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations. TACS employs frequency-specific stimulation of the human brain through current applied to the scalp with surface electrodes. Most current knowledge of the technique is based on behavioral studies; thus, combining the method with brain imaging holds potential to better understand the mechanisms of tACS. Because of electrical and susceptibility artifacts, combining tACS with brain imaging can be challenging, however, one brain imaging technique that is well suited to be applied simultaneously with tACS is functional magnetic resonance imaging (fMRI). In our lab, we have successfully combined tACS with simultaneous fMRI measurements to show that tACS effects are state, current, and frequency dependent, and that modulation of brain activity is not limited to the area directly below the electrodes. This article describes a safe and reliable setup for applying tACS simultaneously with visual task fMRI studies, which can lend to understanding oscillatory brain function as well as the effects of tACS on the brain.

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations, though its effects are not completely understood. This article describes a safe and reliable setup for applying tACS simultaneously with functional magnetic resonance imaging, which can increase understanding oscillatory brain function and effects of tACS.