Down-regulation of theta amplitude through neurofeedback improves executive control network efficiency in healthy children.

Despite extensive clinical research on neurofeedback (NF) in attention-deficit/hyperactivity disorder (ADHD), few studies targeted the optimization of attention performance in healthy children. As a crucial component of attention networks, the executive control network, involved in resolving response conflicts and allocating cognitive resources, is closely linked to theta activity. Here, we aimed to answer whether theta down-regulating NF can enhance healthy children's attention performance, especially the executive control network. Sixty children aged 6-12 years were randomly assigned to the NF and waitlist control groups. The NF group received theta down-regulation NF training for five days (a total of 100 mins), and the attention performance of both groups was measured by the attention network test (ANT) in the pre, post-NF, and 7-day follow-up. The electroencephalographic (EEG) results demonstrated a significant decrease in resting-state theta amplitude within sessions. For the behavioral results, the NF group exhibited significant improvements in overall attention performance and the efficiency of the executive control network relative to the control group in the post-NF and follow-up assessment, whereas the alerting and orienting networks remained unchanged. These findings proved the feasibility of theta down-regulating NF and its positive effect on attention in the healthy children population. In particular, the facilitation of the efficiency of the executive control network and the unaltered performance of the other two attention networks in the NF group may support the causality between theta rhythm and the executive control network.

Predictive role of impulsivity, anxiety, and depression in the efficacy of intermittent theta burst transcranial magnetic stimulation modalities for treating methamphetamine use disorder: A randomized clinical trial.

INTRODUCTION: Methamphetamine use disorder (MUD) can cause impulsive behavior, anxiety, and depression. Stimulation of the left dorsolateral prefrontal cortex in MUD patients by intermittent theta burst repetitive transcranial magnetic stimulation (iTBS-rTMS) is effective in reducing cravings, impulsive behavior, anxiety, and depression. The purpose of this study was to explore whether these psychological factors helped to predict MUD patients' responses to iTBS-rTMS treatment. METHODS: Fifty MUD patients and sixty healthy subjects matched for general conditions were used as study subjects. The study randomly divided MUD patients into iTBS-rTMS and sham stimulation groups and received 20 sessions of real or sham iTBS-rTMS treatment, and the study collected cue-related evoked craving data before and after treatment. All subjects completed the Barratt Impulsiveness Scale (BIS-11), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). RESULTS: The MUD patients showed significantly higher levels of impulsivity, anxiety, and depression than the healthy subjects. The MUD patients who received the real treatment had significantly lower impulsivity, anxiety, and depression scores, and better treatment effects on cravings than the sham stimulation group. The Spearman rank correlation and stepwise multiple regression analyses showed that the baseline BIS-11 and the reduction rate (RR) of BIS-11 and RR of SDS were positively correlated with the decrease in cravings in the iTBS-rTMS group. ROC curve analysis showed that RR of SDS (AUC = 91.6 %; 95 % CI = 0.804-1.000) had predictive power to iTBS- rTMS therapeutic efficacy, the cutoff value is 15.102 %. CONCLUSIONS: iTBS-rTMS had a good therapeutic effect in MUD patients and the baseline impulsivity, the improved depression and impulsivity were associated with therapeutic effect of iTBS-rTMS. The improved depression had the potential to predict the efficacy of the iTBS-rTMS modality for MUD treatment.

Theta EEG neurofeedback promotes early consolidation of real life-like episodic memory.

Theta oscillations are believed to coordinate neuronal activity related to human cognition, especially for memory functions. Theta power during learning and retrieval has been found to correlate with memory performance success. Additionally, up-regulating theta oscillations during a post-encoding epoch crucial for memory consolidation was previously shown to benefit long-term memory for acquired motor sequences, pictures, and object-location associations. However, it remains to be determined whether such effects would be found for more ecological aspects of long-term episodic memory. Therefore, the current study assessed neurofeedback-based theta upregulation effects on movie memory. After viewing a 15-minute silent, narrative movie, participants engaged in neurofeedback-based theta/beta up-regulation, neurofeedback beta/theta up-regulation as an active control condition, or an unrelated passive control task. Memory was tested three times: once immediately after watching the movie (as baseline); 24 hours thereafter; and once again 1 week later. Memory performance 1 week after encoding was significantly enhanced in the theta/beta up-regulation group compared with the other groups. Additionally, changes in neurofeedback theta/beta ratio from baseline EEG recordings correlated with long-term memory gains in retrieving the movie's content. These findings highlight the relationship between post-learning theta oscillations and the consolidation of episodic memory for a naturalistic event.

Self-modulation of the sense of agency via neurofeedback enhances sensory-guided behavioral control.

The sense of agency is a fundamental aspect of human self-consciousness, whose neural correlates encompass widespread brain networks. Research has explored the neuromodulatory properties of the sense of agency with noninvasive brain stimulation, which induces exogenous manipulations of brain activity; however, it is unknown whether endogenous modulation of the sense of agency is also achievable. We investigated whether the sense of agency can be self-regulated with electroencephalography-based neurofeedback. We conducted 2 experiments in which healthy humans performed a motor task while their motor control was artificially disrupted, and gave agency statements on their perceived control. We first identified the electrophysiological response to agency processing, and then applied neurofeedback in a parallel, sham-controlled design, where participants learnt to self-modulate their sense of agency. We found that behavioral measures of agency and performance on the task decreased with the increasing disruption of control. This was negatively correlated with power spectral density in the theta band, and positively correlated in the alpha and beta bands, at central and parietal electrodes. After neurofeedback training of central theta rhythms, participants improved their actual control over the task, and this was associated with a significant decrease in the frequency band trained via neurofeedback. Thus, self-regulation of theta rhythms can improve sensory-guided behavior.

Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex Increases Posterior Theta Rhythm and Reduces Latency of Motor Imagery.

Experiments show activation of the left dorsolateral prefrontal cortex (DLPFC) in motor imagery (MI) tasks, but its functional role requires further investigation. Here, we address this issue by applying repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC and evaluating its effect on brain activity and the latency of MI response. This is a randomized, sham-controlled EEG study. Participants were randomly assigned to receive sham (15 subjects) or real high-frequency rTMS (15 subjects). We performed EEG sensor-level, source-level, and connectivity analyses to evaluate the rTMS effects. We revealed that excitatory stimulation of the left DLPFC increases theta-band power in the right precuneus (PrecuneusR) via the functional connectivity between them. The precuneus theta-band power negatively correlates with the latency of the MI response, so the rTMS speeds up the responses in 50% of participants. We suppose that posterior theta-band power reflects attention modulation of sensory processing; therefore, high power may indicate attentive processing and cause faster responses.

Neural and behavioral adaptations to frontal theta neurofeedback training: A proof of concept study.

Previous neurofeedback research has shown training-related frontal theta increases and performance improvements on some executive tasks in real feedback versus sham control groups. However, typical sham control groups receive false or non-contingent feedback, making it difficult to know whether observed differences between groups are associated with accurate contingent feedback or other cognitive mechanisms (motivation, control strategies, attentional engagement, fatigue, etc.). To address this question, we investigated differences between two frontal theta training groups, each receiving accurate contingent feedback, but with different top-down goals: (1) increase and (2) alternate increase/decrease. We hypothesized that the increase group would exhibit greater increases in frontal theta compared to the alternate group, which would exhibit lower frontal theta during down- versus up-modulation blocks over sessions. We also hypothesized that the alternate group would exhibit greater performance improvements on a Go-NoGo shooting task requiring alterations in behavioral activation and inhibition, as the alternate group would be trained with greater task specificity, suggesting that receiving accurate contingent feedback may be the more salient learning mechanism underlying frontal theta neurofeedback training gains. Thirty young healthy volunteers were randomly assigned to increase or alternate groups. Training consisted of an orientation session, five neurofeedback training sessions (six blocks of six 30-s trials of FCz theta modulation (4-7 Hz) separated by 10-s rest intervals), and six Go-NoGo testing sessions (four blocks of 90 trials in both Low and High time-stress conditions). Multilevel modeling revealed greater frontal theta increases in the alternate group over training sessions. Further, Go-NoGo task performance increased at a greater rate in the increase group (accuracy and reaction time, but not commission errors). Overall, these results reject our hypotheses and suggest that changes in frontal theta and performance outcomes were not explained by reinforcement learning afforded by accurate contingent feedback. We discuss our findings in terms of alternative conceptual and methodological considerations, as well as limitations of this research.

A revised calcium-dependent model of transcranial magnetic theta-burst stimulation.

OBJECTIVE: Calcium dependency is presently an essential assumption in modelling the neuromodulatory effects of transcranial magnetic stimulation. Y.Z.Huang et al.developed the first neuromodulation model to explain the bidirectional effects of theta-burst stimulation (TBS) based on the postsynaptic intracellular calcium concentration elevation. However, we discover that the published computer code is not consistent with the model formulation, neither do the parameters and derived plots consequently match the formulations. Here we intend to fix the computer code and re-calibrate the model. METHODS: We corrected the affected difference equations and re-calibrated the revised model with experimental data using non-convex optimisation based on a L2 penalty. RESULTS: The revised model outperforms the initial model in characterising the relative motor-evoked potential levels of TBS-induced after-effects in various conditions. CONCLUSIONS: We corrected the inconsistencies in the previous model and computer code and provided a complete calibration to support the research that is based on it. SIGNIFICANCE: This work improves the accuracy and secures the scope of the model, which is necessary to retain a rich body of research resulting from the model. Furthermore, this model provides both a quantitative model for several parameters of TBS and a basic model foundation for future refinement.

The role of the primary motor cortex in motor imagery: A theta burst stimulation study.

While mentally simulated actions activate similar neural structures to overt movement, the role of the primary motor cortex (PMC) in motor imagery remains disputed. The aim of the study was to use continuous theta burst stimulation (cTBS) to modulate corticospinal activity to investigate the putative role of the PMC in implicit motor imagery in young adults with typical and atypical motor ability. A randomized, double blind, sham-controlled, crossover, offline cTBS protocol was applied to 35 young adults. During three separate sessions, adults with typical and low motor ability (developmental coordination disorder [DCD]), received active cTBS to the PMC and supplementary motor area (SMA), and sham stimulation to either the PMC or SMA. Following stimulation, participants completed measures of motor imagery (i.e., hand rotation task) and visual imagery (i.e., letter number rotation task). Although active cTBS significantly reduced corticospinal excitability in adults with typical motor ability, neither task performance was altered following active cTBS to the PMC or SMA, compared to performance after sham cTBS. These results did not differ across motor status (i.e., typical motor ability and DCD). These findings are not consistent with our hypothesis that the PMC (and SMA) is directly involved in motor imagery. Instead, previous motor cortical activation observed during motor imagery may be an epiphenomenon of other neurophysiological processes and/or activity within brain regions involved in motor imagery. This study highlights the need to consider multi-session theta burst stimulation application and its neural effects when probing the putative role of motor cortices in motor imagery.

Construction of complex memories via parallel distributed cortical-subcortical iterative integration.

The construction of complex engrams requires hippocampal-cortical interactions. These include both direct interactions and ones via often-overlooked subcortical loops. Here, we review the anatomical organization of a hierarchy of parallel 'Papez' loops through the hypothalamus that are homologous in mammals from rats to humans. These hypothalamic loops supplement direct hippocampal-cortical connections with iterative reprocessing paced by theta rhythmicity. We couple existing anatomy and lesion data with theory to propose that recirculation in these loops progressively enhances desired connections, while reducing interference from competing external goals and internal associations. This increases the signal-to-noise ratio in the distributed engrams (neocortical and cerebellar) necessary for complex learning and memory. The hypothalamic nodes provide key motivational input for engram enhancement during consolidation.

One-Year Follow-Up of Healthy Older Adults with Electroencephalographic Risk for Neurocognitive Disorder After Neurofeedback Training.

BACKGROUND: In healthy older adults, excess theta activity is an electroencephalographic (EEG) predictor of cognitive impairment. In a previous study, neurofeedback (NFB) treatment reinforcing reductions theta activity resulted in EEG reorganization and cognitive improvement. OBJECTIVE: To explore the clinical applicability of this NFB treatment, the present study performed a 1-year follow-up to determine its lasting effects. METHODS: Twenty seniors with excessive theta activity in their EEG were randomly assigned to the experimental or control group. The experimental group received an auditory reward when the theta absolute power (AP) was reduced. The control group received the reward randomly. RESULTS: Both groups showed a significant decrease in theta activity at the training electrode. However, the EEG results showed that only the experimental group underwent global changes after treatment. These changes consisted of delta and theta decreases and beta increases. Although no changes were found in any group during the period between the posttreatment evaluation and follow-up, more pronounced theta decreases and beta increases were observed in the experimental group when the follow-up and pretreatment measures were compared. Executive functions showed a tendency to improve two months after treatment which became significant one year later. CONCLUSION: These results suggest that the EEG and behavioral benefits of this NFB treatment persist for at least one year, which adds up to the available evidence contributing to identifying factors that increase its efficacy level. The relevance of this study lies in its prophylactic features of addressing a clinically healthy population with EEG risk of cognitive decline.

Improving cognitive control: Is theta neurofeedback training associated with proactive rather than reactive control enhancement?

Frontal-midline (FM) theta activity (4-8 Hz) is proposed to reflect a mechanism for cognitive control that is needed for working memory retention, manipulation, and interference resolution. Modulation of FM theta activity via neurofeedback training (NFT) demonstrated transfer to some but not all types of cognitive control. Therefore, the present study investigated whether FM theta NFT enhances performance and modulates underlying EEG characteristics in a delayed match to sample (DMTS) task requiring mainly proactive control and a color Stroop task requiring mainly reactive control. Moreover, temporal characteristics of transfer were explored over two posttests. Across seven 30-min NFT sessions, an FM theta training group exhibited a larger FM theta increase compared to an active control group who upregulated randomly chosen frequency bands. In a posttest performed 13 days after the last training session, the training group showed better retention performance in the DMTS task. Furthermore, manipulation performance was associated with NFT theta increase for the training but not the control group. Contrarily, behavioral group differences and their relation to FM theta change were not significant in the Stroop task, suggesting that NFT is associated with proactive but not reactive control enhancement. Transfer to both tasks at a posttest one day after training was not significant. Behavioral improvements were not accompanied by changes in FM theta activity, indicating no training-induced modulation of EEG characteristics. Together, these findings suggest that NFT supports transfer to cognitive control that manifests late after training but that other training-unspecific factors may also contribute to performance enhancement.

Propagation and update of auditory perceptual priors through alpha and theta rhythms.

To maintain a continuous and coherent percept over time, the brain makes use of past sensory information to anticipate forthcoming stimuli. We recently showed that auditory experience of the immediate past is propagated through ear-specific reverberations, manifested as rhythmic fluctuations of decision bias at alpha frequencies. Here, we apply the same time-resolved behavioural method to investigate how perceptual performance changes over time under conditions of stimulus expectation and to examine the effect of unexpected events on behaviour. As in our previous study, participants were required to discriminate the ear-of-origin of a brief monaural pure tone embedded in uncorrelated dichotic white noise. We manipulated stimulus expectation by increasing the target probability in one ear to 80%. Consistent with our earlier findings, performance did not remain constant across trials, but varied rhythmically with delay from noise onset. Specifically, decision bias showed a similar oscillation at ~9 Hz, which depended on ear congruency between successive targets. This suggests rhythmic communication of auditory perceptual history occurs early and is not readily influenced by top-down expectations. In addition, we report a novel observation specific to infrequent, unexpected stimuli that gave rise to oscillations in accuracy at ~7.6 Hz one trial after the target occurred in the non-anticipated ear. This new behavioural oscillation may reflect a mechanism for updating the sensory representation once a prediction error has been detected.

Delta- and theta-band cortical tracking and phase-amplitude coupling to sung speech by infants.

The amplitude envelope of speech carries crucial low-frequency acoustic information that assists linguistic decoding at multiple time scales. Neurophysiological signals are known to track the amplitude envelope of adult-directed speech (ADS), particularly in the theta-band. Acoustic analysis of infant-directed speech (IDS) has revealed significantly greater modulation energy than ADS in an amplitude-modulation (AM) band centred on ∼2 Hz. Accordingly, cortical tracking of IDS by delta-band neural signals may be key to language acquisition. Speech also contains acoustic information within its higher-frequency bands (beta, gamma). Adult EEG and MEG studies reveal an oscillatory hierarchy, whereby low-frequency (delta, theta) neural phase dynamics temporally organize the amplitude of high-frequency signals (phase amplitude coupling, PAC). Whilst consensus is growing around the role of PAC in the matured adult brain, its role in the development of speech processing is unexplored. Here, we examined the presence and maturation of low-frequency (<12 Hz) cortical speech tracking in infants by recording EEG longitudinally from 60 participants when aged 4-, 7- and 11- months as they listened to nursery rhymes. After establishing stimulus-related neural signals in delta and theta, cortical tracking at each age was assessed in the delta, theta and alpha [control] bands using a multivariate temporal response function (mTRF) method. Delta-beta, delta-gamma, theta-beta and theta-gamma phase-amplitude coupling (PAC) was also assessed. Significant delta and theta but not alpha tracking was found. Significant PAC was present at all ages, with both delta and theta -driven coupling observed.

Evidence for two distinct thalamocortical circuits in retrosplenial cortex.

Retrosplenial cortex (RSC) lies at the interface between sensory and cognitive networks in the brain and mediates between these, although it is not yet known how. It has two distinct subregions, granular (gRSC) and dysgranular (dRSC). The present study investigated how these subregions differ with respect to their electrophysiology and thalamic connectivity, as a step towards understanding their functions. The gRSC is more closely connected to the hippocampal formation, in which theta-band local field potential oscillations are prominent. We, therefore, compared theta-rhythmic single-unit activity between the two RSC subregions and found, mostly in gRSC, a subpopulation of non-directional cells with spiking activity strongly entrained by theta oscillations, suggesting a stronger coupling of gRSC to the hippocampal system. We then used retrograde tracers to test for differential inputs to RSC from the anteroventral thalamus (AV). We found that gRSC and dRSC differ in their afferents from two AV subfields: dorsomedial (AVDM) and ventrolateral (AVVL). Specifically: (1) as a whole AV projects more strongly to gRSC; (2) AVVL targets both gRSC and dRSC, while AVDM provides a selective projection to gRSC, (3) the gRSC projection is layer-specific: AVDM targets specifically gRSC superficial layers. These same AV projections are topographically organized with ventral AV neurons innervating rostral RSC and dorsal AV neurons innervating caudal RSC. These combined results suggest the existence of two distinct but interacting RSC subcircuits: one connecting AVDM to gRSC that may comprise part of the cognitive hippocampal system, and the other connecting AVVL to both RSC regions that may link hippocampal and perceptual regions. We suggest that these subcircuits are distinct to allow for differential weighting during integration of converging sensory and cognitive computations: an integration that may take place in thalamus, RSC, or both.

Effect of visual input on syllable parsing in a computational model of a neural microcircuit for speech processing.

Objective.Seeing a person talking can help us understand them, particularly in a noisy environment. However, how the brain integrates the visual information with the auditory signal to enhance speech comprehension remains poorly understood.Approach.Here we address this question in a computational model of a cortical microcircuit for speech processing. The model consists of an excitatory and an inhibitory neural population that together create oscillations in the theta frequency range. When stimulated with speech, the theta rhythm becomes entrained to the onsets of syllables, such that the onsets can be inferred from the network activity. We investigate how well the obtained syllable parsing performs when different types of visual stimuli are added. In particular, we consider currents related to the rate of syllables as well as currents related to the mouth-opening area of the talking faces.Main results.We find that currents that target the excitatory neuronal population can influence speech comprehension, both boosting it or impeding it, depending on the temporal delay and on whether the currents are excitatory or inhibitory. In contrast, currents that act on the inhibitory neurons do not impact speech comprehension significantly.Significance.Our results suggest neural mechanisms for the integration of visual information with the acoustic information in speech and make experimentally-testable predictions.

Neurofeedback Training Protocol Based on Selecting Distinctive Features to Treat or Reduce ADHD Symptoms.

Recent research has shown that electroencephalography (EEG) theta/beta ratio (TBR) in cases with attention deficit hyperactivity disorder (ADHD) has thus far been reported lower than that in healthy individuals. Accordingly, utilizing EEG-TBR as a biomarker to diagnose ADHD has been called into question. Besides, employing known protocol to reduce EEG-TBR in the vertex (Cz) channel to treat ADHD via neurofeedback (NFB) has been doubted. The present study was to propose a new NFB treatment protocol to manage ADHD using EEG signals from 30 healthy controls and 30 children with ADHD through an attention-based task and to calculate relative power in their different frequency bands. Then, the most significant distinguishing features of EEG signals from both groups were determined via a genetic algorithm (GA). The results revealed that EEG-TBR values in children with ADHD were lower compared with those in healthy peers; however, such a difference was not statistically significant. Likewise, inhibiting alpha band activity and enhancing delta one in F7 or T5 channels was proposed as a new NFB treatment protocol for ADHD. No significant increase in EEG-TBR in the Cz channel among children with ADHD casts doubt on the effectiveness of using EEG-TBR inhibitory protocols in the Cz channel. Consequently, it was proposed to apply the new protocol along with reinforced beta-band activity to treat or reduce ADHD symptoms.

Neurofeedback training improves episodic and semantic long-term memory performance.

Understanding and improving memory are vital to enhance human life. Theta rhythm is associated with memory consolidation and coding, but the trainability and effects on long-term memory of theta rhythm are unknown. This study investigated the ability to improve long-term memory using a neurofeedback (NFB) technique reflecting the theta/low-beta power ratio on an electroencephalogram (EEG). Our study consisted of three stages. First, the long-term memory of participants was measured. In the second stage, the participants in the NFB group received 3 days of theta/low-beta NFB training. In the third stage, the long-term memory was measured again. The NFB group had better episodic and semantic long-term memory than the control group and significant differences in brain activity between episodic and semantic memory during the recall tests were revealed. These findings suggest that it is possible to improve episodic and semantic long-term memory abilities through theta/low-beta NFB training.

Mathematical Modeling of Brain Activity under Specific Auditory Stimulation.

Understanding the connection between different stimuli and the brain response represents a complex research area. However, the use of mathematical models for this purpose is relatively unexplored. The present study investigates the effects of three different auditory stimuli on cerebral biopotentials by means of mathematical functions. The effects of acoustic stimuli (S1, S2, and S3) on cerebral activity were evaluated by electroencephalographic (EEG) recording on 21 subjects for 20 minutes of stimulation, with a 5-minute period of silence before and after stimulation. For the construction of the mathematical models used for the study of the EEG rhythms, we used the Box-Jenkins methodology. Characteristic mathematical models were obtained for the main frequency bands and were expressed by 2 constant functions, 8 first-degree functions, a second-degree function, a fourth-degree function, 6 recursive functions, and 4 periodic functions. The values obtained for the variance estimator are low, demonstrating that the obtained models are correct. The resulting mathematical models allow us to objectively compare the EEG response to the three stimuli, both between the stimuli itself and between each stimulus and the period before stimulation.

Subsequent Acupuncture Reverses the Aftereffects of Intermittent Theta-Burst Stimulation.

Objective: This study explored whether acupuncture affects the maintenance of long-term potentiation (LTP)-like plasticity induced by transcranial magnetic stimulation (TMS) and the acquisition of motor skills following repetitive sequential visual isometric pinch task (SVIPT) training. Methods: Thirty-six participants were recruited. The changes in the aftereffects induced by intermittent theta-burst stimulation (iTBS) and followed acupuncture were tested by the amplitude motor evoked potential (MEP) at pre-and-post-iTBS for 30 min and at acupuncture-in and -off for 30 min. Secondly, the effects of acupuncture on SVIPT movement in inducing error rate and learning skill index were tested. Results: Following one session of iTBS, the MEP amplitude was increased and maintained at a high level for 30 min. The facilitation of MEP was gradually decreased to the baseline level during acupuncture-in and did not return to a high level after needle extraction. The SVIPT-acupuncture group had a lower learning skill index than those in the SVIPT group, indicating that acupuncture intervention after SVIPT training may restrain the acquisition ability of one's learning skills. Conclusion: Acupuncture could reverse the LTP-like plasticity of the contralateral motor cortex induced by iTBS. Subsequent acupuncture may negatively affect the efficacy of the acquisition of learned skills in repetitive exercise training.

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.