Previously, intensity-dependent metabolic changes have been found with positron emission tomography and blood oxygen level dependent magnetic resonance imaging after TMS to motor/prefrontal cortex; bilateral motor/prefrontal and auditory activation is induced, which becomes stronger with increasing pulse intensity [Bohning et al.,1999,2000; Fox et al.,1997; Nahas et al.,2001; Siebner et al.,1999; Speer et al.,2003]. However, these results are not directly comparable with our EEG findings. Arising a few seconds poststimulus, metabolic changes reflect relatively long-lasting activity of interconnected neuronal networks, whereas we were interested in the TMS-evoked events that occurred within a fraction of a second.

It has been established that TMS is most effective in stimulating the motor cortex when the induced current is perpendicular to the central sulcus (Brasil-Neto et al. 1992). This fact suggests that when the optimal MEP site is stimulated, the predominant activation occur in the sulcus.

To date, the monoaminergic (i.e., serotonergic, noradrenergic, dopaminergic) systems in the brain have received the greatest attention in neurobiological studies of mood disorders. These systems project widely to limbic, striatal and prefrontal cortical neuronal circuits that are implicated in the behavioral and visceral manifestations of mood disorders (reviewed in 10–12).

Together, these observations suggest that monoaminergic systems do not represent a final common pathway regulating mood, but rather exert a modulatory influence (see 13 for review).

To test this notion, a recent study investigated the consequences of perturbing slow wave activity. During sleep, EEG was used to record the ongoing brain activity. When slow wave activity increased above a certain threshold, a device started to play sounds. These sounds served to reduce the slow wave activity. After sleep the brain activation following the recall of memories recently acquired was tested. The study demonstrated that MTL activation probed by the memory recall was reduced following the slow wave intervention (Van Der Werf et al., 2009). Using this type of BSDS, it was concluded that slow wave sleep is causally related to memory formation.

It is thus noteworthy that recent studies have shown that the chronic administration of antidepressants can increase synaptic AMPA GluR1 receptors (35, 36).

The rapid antidepressant effects of ketamine have been postulated to occur via AMPA-mediated synaptic potentiation of critical neural circuits (32, 33). Increasing preclinical and clinical evidence demonstrates that synaptic plasticity, a fundamental mechanism of neuronal adaptation, is altered in mood disorders (34).

Using regularized LDA for retraining the classifier after each trial during online operation as in Vidaurre and Blankertz (2010) would hardly be possible without the analytical solution.

Parra et al., 2008, Parra et al., 2003

For a comprehensive review on spatial filters and linear analysis of EEG we refer to Parra et al. (2005) and for a tutorial on optimal spatial filters for features based on oscillatory brain activity (cf. Blankertz et al., 2008c).

Global fluctuations, originating presumably from such systemic effects as respiration and cardiac-induced pulsations, were accounted for individually by orthogonalizing the time-courses with respect to the first three principal components from the white matter voxel time course ensemble and the first three principal components from the time course ensemble of the cerebrospinal fluid (CSF) voxels (Behzadi et al., 2007).

it has been found that cocaine-seeking behavior is associated with increased activity in the projection from the prefrontal cortex to the nucleus accumbens, specifically in the glutamatergic projection from the prelimbic cortex (PL) to the core subcompartment of the nucleus accumbens (NAcore) (McFarland et al., 2003; Rebec & Sun, 2005).

not only does inactivation of either the NAcore or prelimbic cortex prevent cue-, stress-, or cocaine-induced reinstatement of cocaine seeking (McFarland and Kalivas, 2001; McLaughlin and See, 2003; Di Ciano and Everitt, 2004; Fuchs et al., 2004; Di Ciano et al., 2008), but both cocaine- and stress-induced cocaine seeking are associated with a remarkable overflow of synaptic glutamate into the NAcore from prelimbic afferents (McFarland et al., 2003, 2004; Xi et al., 2006; Miguéns et al., 2008).

Rats and mice have a highly developed vomeronasal system and use ultrasonic communication extensively. Much information that is important in the world of the rat or mouse is lost to the investigator. These ultrasonic and chemical signals convey important information to other rats or mice about environmental dangers and how individuals differ from each other. Males and females will respond differently to the signals from conspecifics (e.g., the scent of a male rat might provoke an aggressive response in another male but induce sexual motivation in an estrous female).

Translational human studies based on results from the reinstatement model As mentioned in the “Introduction,” several medications that have been used to treat opiate, nicotine, and alcohol addiction decrease drug priming and cue-induced reinstatement of drug seeking. These findings support the predictive validity of the reinstatement model (Epstein et al. 2006), but they fall short of demonstrating the translational value of the model. This is because the medications were retrospectively assessed in the reinstatement model after they have demonstrated efficacy in human drug addicts. In other words, the medications demonstrated ‘postdictive’ validity, a situation in which effective medications in humans were subsequently found to also be effective in the animal model (Goldstein and Simpson 2002). To date, there are no instances of ‘prospective’ predictive validity with the model; that is, medications/drugs found effective in the reinstatement model that were subsequently found to prevent drug relapse in humans. However, there are several examples of pharmacological similarities between results from rat studies using the reinstatement model and follow-up human laboratory studies on stress-, cue-, and drug-induced craving and other self-report measures, which are to some degree predictive of subsequent drug relapse (Back et al. 2010; Sinha et al. 2006, 2011). We discuss below these examples.

The regional brain activation responses to a stimulant drug also differ between controls and cocaine abusers in ventral prefrontal regions. In control subjects, intravenous stimulant administration decreased the activity of ventral medial frontal regions (OFC and ventral ACC), whereas in cocaine abusers, it activated these regions, which are involved in salience attribution and conditioning (Dosenbach et al., 2006, O’Doherty et al., 2001 and Shackman et al., 2011). Activation of the OFC in cocaine abusers was associated with craving (Volkow et al., 2005). In contrast, activity in the right inferior frontal region Ba 44, a key brain region involved in inhibitory control (Aron et al., 2004), was associated with the deactivation of the NAc and ventral PFC upon successful control of cocaine craving (Volkow et al., 2010). This pattern of responses uncovers distinct contributions of PFC regions to addiction on the basis of their striatal projections: dlPFC and inferior frontal regions that project to the dorsal caudate facilitate self-control, whereas ventral PFC regions projecting to NAc facilitate drug taking (Goldstein and Volkow, 2011). This is also consistent with preclinical findings that identified distinct contributions of prelimbic mPFC (PL) and infralimbic mPFC (IL) to cocaine seeking in rats (review in Bossert et al., 2013). Studies using the reinstatement model of relapse found that, after extinction of cocaine self-administration, PL activity promoted cocaine seeking while IL activity inhibited it (Peters et al., 2008). Importantly, in the incubation of the cocaine-craving model (response to cocaine cues progressively increases with time after withdrawal), reversible inactivation of IL, but not PL, decreased “incubated” cue-induced cocaine seeking after prolonged withdrawal, while pharmacological activation of IL, but not PL, increased cocaine seeking during early withdrawal (Koya et al., 2009). However, in the same animal model, optogenetic inhibition of PL neurons (projecting to NAc core) that previously underwent a specific form of cocaine-induced synaptic plasticity (recruitment of silent synapse) decreased incubation of craving, while the opposite effect was observed following inhibition of the IL projection to NAc shell (Di Forti et al., 2014). In clear contrast, in a punishment-induced suppression model of “compulsive” cocaine seeking, in which most rats suppressed cocaine self-administration by shock punishment while a few did not (punishment-resistant “compulsive” rats), optogenetic stimulation of PL inhibited cocaine seeking in punishment-resistant rats while optogenetic inhibition increased it (Chen et al., 2013). However, in the same model, excitotoxic lesions of the PL or IL had no detectable effect on cocaine seeking in punishment-resistant rats (Pelloux et al., 2013). Taken together, the PL and IL appear to play different and complex roles in cocaine-seeking behaviors in rat addiction models, which are highly dependent on the particular behavior being assessed and the experimental procedure used to manipulate local neuronal activity. The results underscore the complexity of the neuroplasticity within the mPFC circuitry, a multimodal brain structure involved in the orchestration of diverse behaviors.

In contrast, impairment of drug memory following removal of PNNs within the BLA required different timing (Xue et al., 2014).

thereby setting higher standards for experimental protocol/assay design and behavioral analyses and achieving less fragmentary and idiosyncratic descriptions65.

— online outsourcing. Udacity has a network of paid graders across the world who are well versed in each of its courses; when students submit their projects, one of these graders picks up the work and quickly assesses it, including detailed comments about the student’s progress. The graders can earn $50 to $100 an hour.

Such modulation of excitatory input may serve as a mechanism for enhancing the transmission of behaviorally relevant information. As the neostriatum and nucleus accumbens process a wide range of such information, including cognitive, emotional, motivational, motor, and sensory aspects of movement, this mechanism may play an important role in regulating goal-directed behavior.

Rate-meter histograms illustrating responses of striatal (A,D) and accumbal (B,C) neurons to iontophoretic DA (long open boxes) in awake, unrestrained rats.

silent neurons comprise the majority of the striatal neuronal population (∼90–95%)

Interestingly, both the major structures receiving DA input and the primary targets of these structures (i.e. striatum, pallidum, SNR) consist of GABA-containing neurons suggesting the importance of DA–GABA interactions.

(B) Dyn labeling in dyn-IRES-cre x Ai9-tdTomato compared to in situ images from the Allen Institute for Brain Science in a sagittal section highlighting presence of dyn in the striatum, the hippocampus, BNST, amygdala, hippocampus, and substantia nigra. All images show tdTomato (red) and Nissl (blue) staining.(C) Coronal section highlighting dynorphinergic cell labeling in the NAc as compared to the Allen Institute for Brain Science.

in vivo fast-scan cyclic voltammetry

voltammetric recordings

in vitro whole-cell patch clamp

Because cue-evoked DA release developed throughout learning, we examined whether DA release correlated with conditioned-approach behavior. Figure 1E and table S1 show that the ratio of the CS-related DA release to the reward-related DA release was significantly (r2 = 0.68; P = 0.0005) correlated with number of CS nosepokes in a conditioning session (also see fig. S4).

Microdrivable electrode bundles, consisting of 16 or eight 25-μm formvar-coated nichrome microwires

eight wires (50-μm tungsten)

LHb neurons exhibit a high basal firing rate both in slices (Figure 5; Jhou et al., 2013) and in vivo (Bromberg-Martin et al., 2010 and Meier and Herrling, 1993), which likely exerts a tonic inhibitory influence on dopaminergic neurons by activating RMTg GABAergic neurons that directly inhibit VTA dopaminergic neurons. Supporting

Inputs to the LHb arise from forebrain regions including the lateral hypothalamus, entopenduncular nucleus (EN), and prefrontal cortex (Kim and Lee, 2012, Poller et al., 2013, Shabel et al., 2012 and Warden et al., 2012).