Background: Gamma oscillations (30-80 Hz) in the dorsolateral prefrontal cortex (DLPFC) are associated with working memory; a process involving the maintenance and manipulation of information on line (Baddeley, 1986). Gamma oscillations are supported by gamma-aminobutyric acid (GABA) inhibitory interneurons in the DLPFC. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method in which to stimulate the cortex that has been shown to modify oscillations, cognition and GABAergic mechanisms. Patients with schizophrenia have severe deficits in working memory that may be related to impairments in GABAergic inhibitory neurotransmission underlying gamma oscillations in the DLPFC. Objective: First, to evaluate gamma oscillatory activity in patients with schizophrenia during working memory compared to healthy subjects. Second, to examine the effect of rTMS applied over the DLPFC on gamma oscillations generated during working memory in healthy subjects. Third, to examine the effect of rTMS applied to the DLPFC on gamma oscillations in patients with schizophrenia compared to healthy subjects. Hypotheses: First, it was hypothesized that patients with schizophrenia would exhibit an alteration in gamma oscillatory activity. Second, it was hypothesized that rTMS would be effective in enhancing gamma oscillations in healthy subjects. Third, it was hypothesized that rTMS would be effective in inhibiting gamma oscillations in patients with schizophrenia. Results: The first study found that patients with schizophrenia generate excessive gamma oscillations during working memory compared to healthy subjects. The second experiment found that rTMS over the DLPFC resulted in the potentiation of gamma oscillations in healthy subjects during working memory. The third experiment demonstrated that rTMS inhibited excessive gamma oscillations in patients with schizophrenia while an opposite effect was found in healthy subjects. Conclusions: rTMS applied over the DLPFC modulates frontal gamma oscillatory in healthy subjects and in patients with schizophrenia depending on baseline levels of activity, a finding that may ultimately translate into a better understanding of the mechanisms leading to cognitive improvement in this disorder.

Background: Gamma oscillations (30-80 Hz) in the dorsolateral prefrontal cortex (DLPFC) are associated with working memory; a process involving the maintenance and manipulation of information on line (Baddeley, 1986). Gamma oscillations are supported by gamma-aminobutyric acid (GABA) inhibitory interneurons in the DLPFC. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method in which to stimulate the cortex that has been shown to modify oscillations, cognition and GABAergic mechanisms. Patients with schizophrenia have severe deficits in working memory that may be related to impairments in GABAergic inhibitory neurotransmission underlying gamma oscillations in the DLPFC. Objective: First, to evaluate gamma oscillatory activity in patients with schizophrenia during working memory compared to healthy subjects. Second, to examine the effect of rTMS applied over the DLPFC on gamma oscillations generated during working memory in healthy subjects. Third, to examine the effect of rTMS applied to the DLPFC on gamma oscillations in patients with schizophrenia compared to healthy subjects. Hypotheses: First, it was hypothesized that patients with schizophrenia would exhibit an alteration in gamma oscillatory activity. Second, it was hypothesized that rTMS would be effective in enhancing gamma oscillations in healthy subjects. Third, it was hypothesized that rTMS would be effective in inhibiting gamma oscillations in patients with schizophrenia. Results: The first study found that patients with schizophrenia generate excessive gamma oscillations during working memory compared to healthy subjects. The second experiment found that rTMS over the DLPFC resulted in the potentiation of gamma oscillations in healthy subjects during working memory. The third experiment demonstrated that rTMS inhibited excessive gamma oscillations in patients with schizophrenia while an opposite effect was found in healthy subjects. Conclusions: rTMS applied over the DLPFC modulates frontal gamma oscillatory in healthy subjects and in patients with schizophrenia depending on baseline levels of activity, a finding that may ultimately translate into a better understanding of the mechanisms leading to cognitive improvement in this disorder.

Decisions, such as choosing between different rewards, are known to be influenced by a number of variables such as value, uncertainty and delay associated with a rewarding outcome. Various structures in the brain are responsible for handling different aspects of reward related decision making. To understand how such decisions are made, we can attempt to reverse engineer the brain. This involves understanding how brain activity is related to the representation and processing of rewards and also to subsequent behavior in response to rewarding events. One of the central elements of the reward circuitry of the brain is the ventral striatum. It has traditionally been known as the limbic-motor interface and thought to act as a link between various structures in the brain that are responsible for processing reward and reward related behavior. To study the neural processes that underlie processing rewards, I recorded from the ventral striatum of rats as they performed a cue-reward task. The aim of my project was twofold: First, to examine how rats behave in response to changes in value and uncertainty associated with a particular rewarding outcome and second, to investigate how rewards and cues that predict rewards are represented in the neural activity of the ventral striatum. Rats (n=6) were trained on a cue-reward task, where cues indicated the mean or variance of associated outcome distributions. Behavioral responses to the reward predictive cues demonstrated that the rats learned the value and risk associated with subsequent reward outcomes. Ventral striatal gamma oscillations are known to align to rewards in a variety of reward motivated tasks. However, it is not clear if these oscillations are associated with anticipation of obtaining the reward or the reward itself. In previous studies, reward delivery has been correlated with the anticipation of reward. In the current work, a delay is used to distinguish between anticipation of reward and the reward delivery itself. This is achieved by making the rats nose poke for a fixed time interval before the arrival of reward. The analysis presented in this thesis reveals that ventral striatal gamma oscillations occur both during the anticipation and delivery of reward, opening up the possibility of formal tests. They also align to arrival of cues that predict rewarding outcomes. This suggests that gamma oscillations might be essential for modulating behavior in response to cues and rewards both before and after reward delivery. Ventral striatum is ideally situated to modulate behavior in response to rewarding events. Past studies show that ventral striatal neural activity is associated with reward and reward motivated actions. However, as suggested by the research presented in this thesis, it is not clear what specific aspects of the decision making process can be attributed to the ventral striatum once learning in complete. Studying the ventral striatum is important because its malfunctioning is implicated in brain disorders such as drug addiction.

Fast neural oscillations known as beta (12-30Hz) and gamma (30-100Hz) rhythms are recorded across several brain areas of various species. They have been linked to diverse functions like perception, attention, cognition, or interareal brain communication. The majority of the tasks performed by the brain involves communication between brain areas. To efficiently perform communication, mathematical models of brain activity require representing neural oscillations as sustained and coherent rhythms. However, some recordings show that fast oscillations are not sustained or coherent. Rather they are noisy and appear as short and random epochs of sustained activity called bursts. Therefore, modeling such noisy oscillations and investigating their ability to show interareal coherence and phase synchronization are important questions that need to be addressed. In this thesis, we propose theoretical models of noisy oscillations in the gamma and beta bands with the same properties as those observed in in \textit{vivo}. Such models should exhibit dynamic and statistical features of the data and support dynamic phase synchronization. We consider networks composed of excitatory and inhibitory populations. Noise is the result of the finite size effect of the system or the synaptic inputs. The associated dynamics of the Local Field Potentials (LFPs) are modeled as linear equations, sustained by additive and/or multiplicative noises. Such oscillatory LFPs are also known as noise-induced or quasi-cycles oscillations. The LFPs are better described using the envelope-phase representation. In this framework, a burst is defined as an epoch during which the envelope magnitude exceeds a given threshold. Fortunately, to the lowest order, the envelope dynamics are uncoupled from the phase dynamics for both additive and multiplicative noises. For additive noise, we derive the mean burst duration via a mean first passage time approach and uncover an optimal range of parameters for healthy rhythms. Multiplicative noise is shown theoretically to further synchronize neural activities and better explain pathologies with an excess of neural synchronization. We used the stochastic averaging method (SAM) as a theoretical tool to derive the envelope-phase equations. The SAM is extended to extract the envelope-phase equations of two coupled brain areas. The goal is to tackle the question of phase synchronization of noise-induced oscillations with application to interareal brain communication. The results show that noise and propagation delay are essential ingredients for dynamic phase synchronization of quasi-cycles. This suggests that the noisy oscillations recorded in \textit{vivo} and modeled here as quasi-cycles are good candidates for such neural communication. We further extend the use of the SAM to describe several coupled networks subject to white and colored noises across the Hopf bifurcation ie in both quasi-cycle and limit cycle regimes. This allows the description of multiple brain areas in the envelope-phase framework. The SAM constitutes an appropriate and flexible theoretical tool to describe a large class of stochastic oscillatory phenomena through the envelope-phase framework.

Rhythmic oscillations in neuronal activity display variations in amplitude (power) over a range of frequencies. Attention and cognitive performance correlate with increases in cortical gamma oscillations (40-70Hz) that are generated by the coordinated firing of glutamatergic pyramidal neurons and GABAergic interneurons, and are modulated by dopamine. In the medial prefrontal cortex (mPFC) of rats, gamma power increases during treadmill walking, or after administration of an acute subanesthetic dose of the NMDA receptor antagonist ketamine. Ketamine is also used to mimic symptoms of schizophrenia, including cognitive deficits, in healthy humans and rodents. Additionally, the ability of a drug to modify ketamine-induced gamma power has been proposed to predict its pro-cognitive therapeutic efficacy. However, the mechanism underlying ketamine-induced gamma oscillations is poorly understood. We hypothesized that gamma oscillations induced by walking and ketamine would be generated by a shared mechanism in the mPFC and one of its major sources of innervation, the mediodorsal thalamus (MD). Recordings from chronically implanted electrodes in rats showed that both treadmill walking and ketamine increased gamma power, firing rates, and spike-gamma LFP correlations in the mPFC. By contrast, in the MD, treadmill walking increased all three measures, but ketamine decreased firing rates and spike-gamma LFP correlations while increasing gamma power. Therefore, walking- and ketamine-induced gamma oscillations may arise from a shared circuit in the mPFC, but different circuits in the MD. Recent work in normal animals suggests that dopamine D4 receptors (D4Rs) synergize with the neuregulin/ErbB4 signaling pathway to modulate gamma oscillations and cognitive performance. Consequently, we hypothesized that drugs targeting the D4Rs and ErbB receptors would show pro-cognitive potential by reducing ketamine-induced gamma oscillations in mPFC. However, when injected before ketamine, neither the D4R agonist nor antagonist altered ketamine’s effects on gamma power or firing rates in the mPFC, but the pan-ErbB antagonist potentiated ketamine’s increase in gamma power, and prevented ketamine from increasing firing rates. This indicates that D4Rs and ErbB receptors influence gamma power via distinct mechanisms that interact with NMDA receptor antagonism differently. Our results highlight the value of using ketamine-induced changes in gamma power as a means of testing novel pharmaceutical agents.

Oscillations in the brain’s electrical potential, recorded through the technique of electroencephalography (EEG), reflect the ensemble activity of a large population of neurons. Auditory steady-state response (ASSR) is the time-locked entrainment in EEG to an auditory stimulus such as a train of clicks. ASSR to a 40 Hz (gamma frequency) click train is especially reduced in schizophrenia patients, reflecting the sensory processing deficits that impact real-world functional outcomes. Since the 40 Hz ASSR is demonstrable across species and is responsive to pharmacological treatments, it can be a translational biomarker for drug development studies. Prototypical antipsychotic drugs (APDs) like haloperidol and clozapine are examples of typical and atypical classes used to treat schizophrenia patients. While both are D2 receptor blockers, they have additional pharmacological effects that may differentiate them. Here, we investigated the acute effect of clozapine (atypical) or haloperidol (typical) on the 40 Hz ASSR, in two independent studies. The doses for the two drugs were chosen to reflect comparable in vivo D2 receptor occupancy. We used female Sprague-Dawley rats implanted with epidural EEG recording electrodes. In the first experiment, vehicle or clozapine 2.5, 5, and 10 mg/kg were administered (sc) and the 40 Hz ASSR paradigm (65 dB, 40 clicks for 1 second, 2-sec inter-stimulus interval) was used to record responses at 30, 60, 90 and 120 minutes post-drug. Resting-state EEG was recorded at 60 minutes post-treatment. Treatment effects were evaluated on the evoked power and phase-locking factor (PLF), a measure of trial-to-trial consistency of the 40 Hz ASSR. Clozapine improved both measures in a dose and time-dependent manner. Clozapine also tended to reduce the resting-state gamma (30-100 Hz) power, a hallmark of cortical noise. However, the effect was not significant (P>0.05). Next, we tested the effect of haloperidol on the 40 Hz ASSR. Doses of 0.02 mg/kg -0.08 mg/kg (sc) were evaluated at 30, 60, 90 and 120-minutes post-injection. Haloperidol failed to improve the 40 Hz ASSR (evoked power and PLF). Moreover, it had no discernible effect on the resting-state gamma. These results show that despite the comparable blockade of D2 receptors, the putative target for these APDs, clozapine, and haloperidol have different effects on the 40 Hz ASSR. We conclude that the effects of clozapine on 40 Hz ASSR may be unrelated to its affinity to D2 receptors and may be mediated through other pharmacological mechanisms.

Rationale: Schizophrenia patients consistently show deficits in sensory-evoked broadband gamma oscillations and click-evoked entrainment at 40 Hz, called the 40-Hz auditory steady-state response (ASSR). Since such evoked oscillations depend on cortical N-methyl D-aspartic acid (NMDA)-mediated network activity, they can serve as pharmacodynamic biomarkers in the preclinical and clinical development of drug candidates engaging these circuits. However, there are few test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms. Objective: We investigated the long-term psychometric stability of these measures in a rodent model. Methods: Female rats with chronic epidural implants were used to record tone- and 40 Hz click-evoked responses at multiple time points and across six sessions, spread over 3 weeks. We assessed reliability using intraclass correlation coefficients (ICC). Separately, we used mixed-effects ANOVA to examine time and session effects. Individual subject variability was determined using the coefficient of variation (CV). Lastly, to illustrate the importance of long-term measure stability for within-subject testing design, we used low to moderate doses of an NMDA antagonist MK801 (0.025–0.15 mg/kg) to disrupt the evoked response. Results: We found that 40-Hz ASSR showed good reliability (ICC=0.60–0.75), while the reliability of tone-evoked gamma ranged from poor to good (0.33–0.67). We noted time but no session effects. Subjects showed a lower variance for ASSR over tone-evoked gamma. Both measures were dose-dependently attenuated by NMDA antagonism. Conclusion: Overall, while both evoked gamma measures use NMDA transmission, 40-Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.

Gamma oscillations of local field potentials (LFP) in the basal ganglia and thalamus had not been studied during saccades. Eleven patients were studied during deep brain stimulation (DBS); 6 were in the subthalamic nucleus (STN); 3 in the globus pallidus interna (GPi); and 2 in the thalamic ventralis intermedius nucleus (Vim). Patients performed horizontal saccades to visual targets while LFPs from DBS electrodes, scalp electroencephalogram (EEG), and electrooculogram (EOG) were recorded. Wavelet spectrograms were generated and saccade onset and event-related gamma synchronizations (ERS) were compared to baseline without eye motion. ERS were recorded at and after saccade onset in the STN, GPi and Vim, EEGs and EOGs; but were absent during target light illumination without saccades. ERS were symmetric in all DBS contacts and appeared identical in DBS LFPs, frontal EEGs and EOGs. These findings indicate their origin from extraocular muscle spike potentials rather than brain neural activity.