The neurochemical basis of human cortical auditory processing: combining proton magnetic resonance spectroscopy and magnetoencephalography

BACKGROUND: A combination of magnetoencephalography and proton magnetic resonance spectroscopy was used to correlate the electrophysiology of rapid auditory processing and the neurochemistry of the auditory cortex in 15 healthy adults. To assess rapid auditory processing in the left auditory cortex, the amplitude and decrement of the N1m peak, the major component of the late auditory evoked response, were measured during rapidly successive presentation of acoustic stimuli. We tested the hypothesis that: (i) the amplitude of the N1m response and (ii) its decrement during rapid stimulation are associated with the cortical neurochemistry as determined by proton magnetic resonance spectroscopy. RESULTS: Our results demonstrated a significant association between the concentrations of N-acetylaspartate, a marker of neuronal integrity, and the amplitudes of individual N1m responses. In addition, the concentrations of choline-containing compounds, representing the functional integrity of membranes, were significantly associated with N1m amplitudes. No significant association was found between the concentrations of the glutamate/glutamine pool and the amplitudes of the first N1m. No significant associations were seen between the decrement of the N1m (the relative amplitude of the second N1m peak) and the concentrations of N-acetylaspartate, choline-containing compounds, or the glutamate/glutamine pool. However, there was a trend for higher glutamate/glutamine concentrations in individuals with higher relative N1m amplitude. CONCLUSION: These results suggest that neuronal and membrane functions are important for rapid auditory processing. This investigation provides a first link between the electrophysiology, as recorded by magnetoencephalography, and the neurochemistry, as assessed by proton magnetic resonance spectroscopy, of the auditory cortex

Magnetoencephalography as a Putative Biomarker for Alzheimer's Disease

Alzheimer's Disease (AD) is the most common dementia in the elderly and is estimated to affect tens of millions of people worldwide. AD is believed to have a prodromal stage lasting ten or more years. While amyloid deposits, tau filaments, and loss of brain cells are characteristics of the disease, the loss of dendritic spines and of synapses predate such changes. Popular preclinical detection strategies mainly involve cerebrospinal fluid biomarkers, magnetic resonance imaging, metabolic PET scans, and amyloid imaging. One strategy missing from this list involves neurophysiological measures, which might be more sensitive to detect alterations in brain function. The Magnetoencephalography International Consortium of Alzheimer's Disease arose out of the need to advance the use of Magnetoencephalography (MEG), as a tool in AD and pre-AD research. This paper presents a framework for using MEG in dementia research, and for short-term research priorities

Effects of 12-Week Bacopa monnieri

At present, the scientific evidence concerning the effect of Bacopa monnieri on brain activity together with working memory is less available. Therefore, we aimed to determine the effect of B. monnieri on attention, cognitive processing, working memory, and cholinergic and monoaminergic functions in healthy elderly. A randomized double-blind placebo-controlled design was utilized. Sixty healthy elderly subjects (mean age 62.62 years; SD 6.46), consisting of 23 males and 37 females, received either a standardized extract of B. monnieri (300 and 600 mg) or placebo once daily for 12 weeks. The cholinergic and monoaminergic systems functions were determined using AChE and MAO activities. Working memory was assessed using percent accuracy and reaction time of various memory tests as indices, whereas attention and cognitive processing were assessed using latencies and amplitude of N100 and P300 components of event-related potential. All assessments were performed before treatment, every four weeks throughout study period, and at four weeks after the cessation of intervention. B. monnieri-treated group showed improved working memory together with a decrease in both N100 and P300 latencies. The suppression of plasma AChE activity was also observed. These results suggest that B. monnieri can improve attention, cognitive processing, and working memory partly via the suppression of AChE activity

Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function

The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (N = 81 each), we used a double-blind placebo-controlled between-subject design to systematically test whether auditory mismatch responses under varying levels of environmental stability are sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. We found a significant drug × mismatch interaction: while the muscarinic acetylcholine receptor antagonist biperiden delayed and topographically shifted mismatch responses, particularly during high stability, this effect could not be detected for amisulpride, a dopamine D2/D3 receptor antagonist. Neither galantamine nor levodopa, which elevate acetylcholine and dopamine levels, respectively, exerted significant effects on MMN. This differential MMN sensitivity to muscarinic versus dopaminergic receptor function may prove useful for developing tests that predict individual treatment responses in schizophrenia

Sounds in noise: Behavioral and neural studies of illusory continuity and discontinuity

ability to parse an auditory scene into meaningful components varies greatly between individuals; some are able to parse out and write down competing musical pieces while others struggle to understand each word whenever they have to converse in a noisy environment. Using a simple discrimination task, healthy, normally-heari ng adult participants were asked to judge whether a pure tone (with or without amplitude modulation) was continuous or contained a gap. One quarter of the participants consistently heard a gap when none was present, if the tone was accompanied by a higher-frequency noise burst with a lower edge beginning one octave away from the tone (that did not have any energy overlapping the tone). This novel form of informational masking (perceptual interference between components with non-overlapping sound energy) was named 'illusory auditory discontinuity\u2019. The phenomenon appears to reflect natural differences in auditory processing rather than differences in decision-making strategies because: (1) susceptibility to illusory discontinuity correlates with individual differences in auditory streaming (measured using a classical ABA sequential paradigm); and (2) electroencephalographic responses elicited by tones overlaid by short noise bursts (when these sounds are not the focus of attention) are significantly correlated with the occurrence of illusory auditory discontinuity in both an early event-related potential (ERP) component (40-66 ms), and a later ERP component (270-350 ms) after noise onset. Participants prone to illusory discontinuity also tended not to perceive the \u2018auditory continuity illusion\u2019 (in which a tone is heard continuing under a burst of noise centered on the tone frequency that completely masks it) at short noise durations, but reliably perceived the auditory continuity illusion at longer noise durations. These results suggest that a number of attributes describing how individuals differentially parse complex auditory scenes are related to individual differences in two potentially independent attributes of neural processing, reflected here by EEG waveform differences at ~50 msec and ~300 msec after noise onset. Neural correlates of the auditory continuity illusion were also investigated by adjusting masker loudness, so that when listeners were given physically identical stimuli, they correctly detected the gap in a target tone on some trials, while on other trials they reported the tone as continuous (experiencing illusory continuity). High er power of low-frequency EEG activity (in the delta-theta range, <6 Hz) was observed prior to the onset of tones that were subsequently judged as discontinuous, with no other consistent EEG differences found after the onset of tones. These data suggest that the occurrence of the continuity illusion may depend on the brain state that exists immediately before a trial begins

Causal modelling of evoked brain responses.

The aim of this thesis was to test predictive coding as a model of cortical organization and function using a specific brain response, the mismatch negativity (MMN), and a novel tool for connectivity analysis, dynamic causal modelling (DCM). Predictive coding models state that the brain perceives and makes inferences about the world by recursively updating predictions about sensory input. Thus, perception would result from comparing bottom-up input from the environment with top-down predictions. The generation of the MMN, an event- related response elicited by violations in the regularity of a structured auditory sequence, has been discussed extensively in the literature. This thesis discusses the generation of the MMN in the light of predictive coding, in other words, the MMN could reflect prediction error, occurring whenever the current input does not match a previously learnt rule. This interpretation is tested using DCM, a methodological approach which assumes the activity in one cortical area is caused by the activity in another cortical area. In brief, this thesis assesses the validity of DCM, shows the usefulness of DCM in explaining how cortical activity is expressed at the scalp level and exploits the potential of DCM for testing hierarchical models underlying the MMN. The first part of this thesis is concerned with technical issues and establishing the validity of DCM. The second part addresses hierarchical cortical organization in MMN generation, plausible network models or mechanisms underlying the MMN, and finally, the effect of repetition or learning on the connectivity parameters of the causal model

Mismatch responses in the awake rat: Evidence from epidural recordings of auditory cortical fields

The detection of sudden alterations in a rapidly changing environment is crucial for the survival of humans and animals. In the human auditory system the mismatch negativity (MMN), a special component of auditory evoked potentials (AEPs), reflects the violation of predictable stimulus regularities, established by the previous auditory sequence. Given the considerable potential of the human MMN for clinical applications, i.e. several diseases are associated with decreased MMN, the development of animal models that allow for detailed investigation of the underlying neurophysiological mechanisms is necessary. Rodent studies were so far almost exclusively conducted under anesthesia and have not provided decisive evidence whether an MMN analogue exists in rats. This may be due to several factors, most importantly, however, the effect of anesthesia. In the present thesis, epidural recordings in awake black hooded rats were conducted to investigate whether an analogue to human MMN exists in rats. AEPs to bandpass filtered noise stimuli that were optimized in frequency and duration were recorded bilaterally from two auditory cortical areas. Using a classical oddball paradigm with frequency deviants, mismatch responses were detected in primary (A1) and secondary auditory cortex, namely the posterior auditory field (PAF). Those responses share key properties with the human MMN, i.e. large amplitude biphasic differences that increased in amplitude with decreasing deviant probability. For distinguishing between adaptation and other mechanisms that may explain MMN like phenomena like deviance detection or prediction error signaling, several control conditions were conducted. Converging probability of deviant and standard stimuli for example led to a disappearance of the overall difference between both potentials. This may be due to adaptation affecting also deviant potentials due to the high number of stimuli presented. On the other hand, arguing with prediction error signaling, the presented sequence may not have allowed the brain to establish a prediction about the upcoming sequence in general thus generating prediction errors for both stimuli. The complete omission of deviant sounds in an otherwise homogenous sequence did not lead to evoked activity. Furthermore, in a control condition that removed the predictive context while controlling for the presentation rate of deviants MMN like activity diminished. This finding may suggest that mismatch responses are even partly generated by deviance detection or prediction error signaling. However, the chosen experimental design does not allow for disambiguating precisely the overall contribution of adaptation and other mechanisms that may explain MMN generation to the observed responses. In addition, a modeling approach was conducted using dynamic causal modeling (DCM) in order to differentiate between the above mentioned mechanisms. The results suggest that adaptation is a key factor for the generation of mismatch responses in awake rats. DCM also revealed evidence for a second mechanism, namely synaptic plasticity. Synaptic plasticity was suggested as underlying mechanism responsible for establishing a prediction about upcoming stimuli by learning the standards and signaling this and related prediction errors across hierarchically organized brain areas. In order to investigate whether spike frequency adaptation underlies MMN generation, a pharmacological alteration of this mechanism via the manipulation of muscarinic acetylcholine receptors was intended, accompanied by the detection of the resulting changes with DCM. Therefore, an agonist (pilocarpine) and antagonist (scopolamine) of the muscarinic receptor were applied. Mismatch responses were preserved after the injection of muscarinic drugs while a change of spike frequency adaptation was not observed. Although results from vehicle treated animals resemble previous modeling results, DCM could not further contribute to the assessment of the impact of spike frequency adaptation to the generation of MMN like potentials. However, it has been shown that cholinergic signaling is involved in the generation of AEPs elicited with an oddball paradigm in awake rats. Scopolamine was shown to enhance the overall potential waveform whereas pilocarpine led to a reduction of AEPs. This study demonstrates that robust MMN like responses can be obtained in awake and unrestrained rats and therefore provides a basis for future experimental investigations of the mechanisms that underlie MMN generation. Establishing anesthesia-independent settings for probing rodent analogues to human MMN are important for facilitating the detection of therapeutic targets at the cellular level. Knowledge of these targets may guide the development of drugs for treating disorders that have been shown to be accompanied by reduced MMN responses