Validation of the 40 Hz Auditory Steady State Response as a Pharmacodynamic Biomarker of Evoked Neural Synchrony

Schizophrenia is a troubling and severe mental illness that is only incompletely treated by currently available drugs. New drug development is hindered by a scarcity of functionally relevant pharmacodynamic biomarkers that are translatable across preclinical and human subjects. Although psychosis is a major feature of schizophrenia, cognitive and negative symptoms determine the long-term functional outcomes for patients. Stimulus-evoked neural synchrony at gamma (~ 40 Hz) frequency plays an important role in the processing and integration of sensory information. Not surprisingly, schizophrenia patients show deficits in gamma oscillations. NMDA receptor (NMDAR) activation on fast-spiking parvalbumin-positive interneurons is deemed important for the generation of gamma oscillations. NMDA hypofunction has been proposed as an alternative hypothesis to the well-known dopamine dysregulation to explain the neurochemical abnormalities associated with schizophrenia. For this dissertation, we validated a preclinical model to pharmacologically probe NMDA-mediated gamma oscillations by further characterizing the auditory-steady state response (ASSR) in female Sprague Dawley rats. The ASSR is a measure of cortical neural synchrony evoked in response to periodic auditory stimuli. ASSR at 40 Hz is consistently disrupted in patients. First, we established the reliability of click train-evoked 40 Hz ASSR and tone-evoked gamma oscillations in 6 separate sessions, spread over a 3-week period. Then we established the sensitivity of these neural synchrony measures to acute NMDAR blockade using the high affinity NMDA channel blocker MK-801, using a repeated measures design. Next, we compared the reliability and sensitivity of the 40 Hz ASSR from two distinct recording sites. Results from this study showed that as compared to vertex, temporal recording showed a greater gamma synchrony. However, the temporal recording had poor test-retest reliability and lower sensitivity to MK-801-induced disruption. Lastly, we characterized the dose-response profiles of an NMDA co-agonist D-serine, an atypical (clozapine) and a typical (haloperidol) antipsychotic, on the 40 Hz ASSR. Results from these studies showed that only clozapine was effective in robustly augmenting 40 Hz ASSR. Furthermore, only clozapine pretreatment had partial protective effect against MK-801 induced ASSR disruption. Overall, this work establishes that vertex recorded 40 Hz ASSR is a reliable neural synchrony biomarker in female SD rats that is amenable for bidirectional pharmacodynamic modulation

Effects of theta-frequency binaural beats on post-exercise recovery and stress responsivity

Binaural beats are an auditory illusion perceived when two or more pure tones of similar frequencies are presented dichotically through stereo headphones. This phenomenon is thought to have the potential to facilitate changes in arousal. The present study investigated the effects of 7 Hz binaural beating on post-exercise recovery and stress responsivity in college-aged students (n = 21; 18-29 years old).Theta binaural beats failed to outperform placebo in altering post-exercise recovery or stress responsivity. However, after listening to binaural beats, participants reported feeling more relaxed (6.4% change) and less stressed (11.5% change). Findings from the present study suggest that listening to binaural beats may have subtle psychological effects

Terapias auditivas para acúfenos (tinnitus)

Un acúfeno (tinnitus) es la percepción de un sonido en ausencia de estimulación acústica externa, es decir, la experiencia consciente de un sonido que se origina en la propia cabeza del paciente. En colaboración con el departamento de acústica (CAEND) del Consejo Superior de Investigaciones Científicas (CSIC), se pretende revertir (de forma paliativa) las molestias, con ayuda de terapias sonoras que estimulan el sistema auditivo. Primero, se analizan los tratamientos existentes que se utilizan para atender a los pacientes diagnosticados. Por último, se diseñan dos aplicaciones informáticas referentes a las terapias: Auditory Discrimination Training (ADT) y Enriched Acoustic Environment (EAE). Abstract Tinnitus is the perception of sound in the absence of external acoustic stimulation, in addition, the conscious experience a sound originating from the patient’s own head. In collaboration with the department of acoustic (CAEND) of the Consejo Superior de Investigaciones Científicas (CSIC), is to reverse (for palliation) discomfort, using sound therapies that stimulate the auditory system. First, we analyze the existing treatments are used to treat patients diagnosed. Finally, two applications are designed regarding therapies: Auditory Discrimination Training (ADT) and Enriched Acoustic Environment (EAE)

Familiarity-related neuronal responses under normal conditions and in an animal model of mental illness

Recognition memory is one of the most basic types of memory. One type of recognition memory is visual familiarity, which is the sense that a visual stimulus has been encountered before. This type of memory is affected in different mental illnesses, like schizophrenia and autism. The perirhinal cortex, which is a part of the medial temporal lobe has long been believed to be crucial for recognition. This work had 2 main lines of research. The first part, described in chapters Chapter 3 and Chapter 4 , set out to investigate whether activity at either the population level or at the single-unit level in the mouse perirhinal cortex was correlated with visual familiarity. In these chapters, the recordings were made also in the visual cortex and the hippocampus to put the perirhinal response in the context of the activity both upstream and downstream from it, respectively. Visual stimuli evoked responses in the perirhinal cortex, no familiarity-related modulation could be detected at both levels of analysis. That was true even when the visual cortex demonstrated familiarity-related differences in response. The second part of the work, described in chapters Chapter 5 and Chapter 6 examined the mice with haplo-insufficiency of the CYFIP1 gene as a possible new model for mental illness. First, the animal’s validity as a model of mentalillness was tested using auditory-evoked potential, one of the most ubiquitous phenomena that appears with mental illness in people and animal models. Then, recognition memory and the neuronal activity in the perirhinal and the visual cortex was tested, to see if they demonstrate other symptoms relating to schizophrenia. In the second line of work, the CYFIP1 mice demonstrated an auditory-evoked potential profile more like that observed in fragile-X syndrome, rather than schizophrenia and did not present any changes in both recognition memory or the electrical activity in the visual and the perirhinal cortex. This work showed that the perirhinal cortex does not show any familiarity-related activity unlike the current assumption in the literature. It also showed that the CYFIP1 mice might be a possible model for autism and Fragile-X syndrome

Characterising mismatch negativity biomarker signatures in preclinical models relevant to schizophrenia

Mismatch negativity (MMN) has been hailed as a "break-through biomarker in predicting psychosis onset" (Naatanen 2015). This is because deficits have been found in clinical populations diagnosed with psychotic syndromes such as schizophrenia. MMN is an auditory evoked potential (AEP) difference waveform produced by subtracting standard from deviant stimuli AEPs elicited by an oddball paradigm; purportedly arising from any discriminable change in auditory stimulation.;Despite nearly four decades of basic research into MMN the underlying mechanisms are not fully understood. Although popular theories suggest that it reflects a sensory-memory trace disruption and/or differential adaptation of responses to standard and deviant/oddball stimuli, there remains considerable debate over the neural mechanism and its interpretation.;Nevertheless, associations made between N-methyl-d-aspartate (NMDA) receptors in schizophrenia and findings showing that NMDA receptor antagonists (e.g. ketamine) induce MMN deficits in healthy volunteers suggests abnormal MMNs share common traits and support its use as a biomarker from an electrophysiological perspective. However, this is still speculative and there is great impetus on developing reliable preclinical models of MMN in order to examine the underpinning neurophysiology and therefore its reliance on NMDA receptors as a test of pathology in schizophrenia.;A question this thesis aims to address is whether a mismatch response (MMR) exists in rodents which is analogous to the human MMN, and whether its modification by NMDA receptor antagonists or as a result of schizophrenia-related genetic modification sheds light on its utility as a biomarker in disease models of schizophrenia.;This thesis describes three experiments performed using mitogen activated protein kinase kinase 7 heterozygous (Map2k7+/−) mice and their wild-type littermates, incorporating NMDA receptor antagonism with ketamine (10 mg/kg i.p.). The MAP2K7 gene is associated with schizophrenia and codes for a post-synaptic intracellular signalling enzyme which is activated following glutamatergic excitation, for instance via NMDA receptors.;The MMR to stimuli duration, frequency and intensity changes in oddball paradigms are characterised in urethane-anaesthetised and conscious animals, followed by an examination of laminar auditory cortex activity in response to these physical changes. Data recorded throughout this series of experiments includes cortical electroencephalography (EEG), video footage, and intra-cortical spiking information. These data were then analysed using various time, frequency and time-frequency domain techniques; although mainly focussing on the event-related potential (ERP) approach.;Recordings demonstrated substantial differences in the AEP waveform evoked from urethane-anaesthetised and conscious animals, with the latter displaying considerably more dynamic responses, although onset and offset of auditory stimuli induced comparable waveform features in both states. Effects of varying physical properties of stimuli in oddball and control paradigms have been identified as key determinants of the AEP and correspondingly the MMR difference waveform amplitudes.;The finding that NMDA receptor disruption in conscious animals by ketamine acutely diminishes a specific AEP feature (≈20-50 ms post stimulus onset) which may impact the resulting MMR tentatively links this study in mice with findings from humans noted above. Ketamine was also found to enhance animal movement and increase EEG spectral power in the 50-70 Hz (gamma-band) frequency range, observed for approximately 10 minutes following drug administration.;Both anaesthetised and conscious cohorts of Map2k7+/− mice displayed a significantly enhanced onset response (≈0-20 ms) in the AEP. Interestingly, ketamine did not appear to have a differential effect on Map2k7+/− mice compared with the wild-type group, suggesting that NMDA receptor-mediated neurotransmission is unimpaired in this genetic model relevant to schizophrenia.;Overall, the findings suggest that the MMR in mice is fundamentally influenced by the physical properties of stimuli employed; ketamine causes an acute, specific alteration to the AEP in conscious mice in addition to other electrophysiological and behavioural changes; and Map2k7 gene disruption causes a specific and replicable change in AEP amplitude.;Overall this study indicates that mouse models are useful for exploring the effects of different pharmacological and genetic manipulations on the auditory evoked response; however, MMN data in clinical cohorts still needs to be interpreted with care. In order to address whether the rodent MMR is analogous to human MMN, it would be necessary to probe how influencing factors revealed in the rodent studies impact on the human response. Whilst the rodent MMR and human MMN show some degree of translation, their potential as schizophrenia biomarkers requires further characterisation and validation.Mismatch negativity (MMN) has been hailed as a "break-through biomarker in predicting psychosis onset" (Naatanen 2015). This is because deficits have been found in clinical populations diagnosed with psychotic syndromes such as schizophrenia. MMN is an auditory evoked potential (AEP) difference waveform produced by subtracting standard from deviant stimuli AEPs elicited by an oddball paradigm; purportedly arising from any discriminable change in auditory stimulation.;Despite nearly four decades of basic research into MMN the underlying mechanisms are not fully understood. Although popular theories suggest that it reflects a sensory-memory trace disruption and/or differential adaptation of responses to standard and deviant/oddball stimuli, there remains considerable debate over the neural mechanism and its interpretation.;Nevertheless, associations made between N-methyl-d-aspartate (NMDA) receptors in schizophrenia and findings showing that NMDA receptor antagonists (e.g. ketamine) induce MMN deficits in healthy volunteers suggests abnormal MMNs share common traits and support its use as a biomarker from an electrophysiological perspective. However, this is still speculative and there is great impetus on developing reliable preclinical models of MMN in order to examine the underpinning neurophysiology and therefore its reliance on NMDA receptors as a test of pathology in schizophrenia.;A question this thesis aims to address is whether a mismatch response (MMR) exists in rodents which is analogous to the human MMN, and whether its modification by NMDA receptor antagonists or as a result of schizophrenia-related genetic modification sheds light on its utility as a biomarker in disease models of schizophrenia.;This thesis describes three experiments performed using mitogen activated protein kinase kinase 7 heterozygous (Map2k7+/−) mice and their wild-type littermates, incorporating NMDA receptor antagonism with ketamine (10 mg/kg i.p.). The MAP2K7 gene is associated with schizophrenia and codes for a post-synaptic intracellular signalling enzyme which is activated following glutamatergic excitation, for instance via NMDA receptors.;The MMR to stimuli duration, frequency and intensity changes in oddball paradigms are characterised in urethane-anaesthetised and conscious animals, followed by an examination of laminar auditory cortex activity in response to these physical changes. Data recorded throughout this series of experiments includes cortical electroencephalography (EEG), video footage, and intra-cortical spiking information. These data were then analysed using various time, frequency and time-frequency domain techniques; although mainly focussing on the event-related potential (ERP) approach.;Recordings demonstrated substantial differences in the AEP waveform evoked from urethane-anaesthetised and conscious animals, with the latter displaying considerably more dynamic responses, although onset and offset of auditory stimuli induced comparable waveform features in both states. Effects of varying physical properties of stimuli in oddball and control paradigms have been identified as key determinants of the AEP and correspondingly the MMR difference waveform amplitudes.;The finding that NMDA receptor disruption in conscious animals by ketamine acutely diminishes a specific AEP feature (≈20-50 ms post stimulus onset) which may impact the resulting MMR tentatively links this study in mice with findings from humans noted above. Ketamine was also found to enhance animal movement and increase EEG spectral power in the 50-70 Hz (gamma-band) frequency range, observed for approximately 10 minutes following drug administration.;Both anaesthetised and conscious cohorts of Map2k7+/− mice displayed a significantly enhanced onset response (≈0-20 ms) in the AEP. Interestingly, ketamine did not appear to have a differential effect on Map2k7+/− mice compared with the wild-type group, suggesting that NMDA receptor-mediated neurotransmission is unimpaired in this genetic model relevant to schizophrenia.;Overall, the findings suggest that the MMR in mice is fundamentally influenced by the physical properties of stimuli employed; ketamine causes an acute, specific alteration to the AEP in conscious mice in addition to other electrophysiological and behavioural changes; and Map2k7 gene disruption causes a specific and replicable change in AEP amplitude.;Overall this study indicates that mouse models are useful for exploring the effects of different pharmacological and genetic manipulations on the auditory evoked response; however, MMN data in clinical cohorts still needs to be interpreted with care. In order to address whether the rodent MMR is analogous to human MMN, it would be necessary to probe how influencing factors revealed in the rodent studies impact on the human response. Whilst the rodent MMR and human MMN show some degree of translation, their potential as schizophrenia biomarkers requires further characterisation and validation