Cognitive Impairment Associated with Schizophrenia: From Pathophysiology to Treatment.

Cognitive impairment is a core feature of schizophrenia and a major contributor to poor functional outcomes. Methods for assessment of cognitive dysfunction in schizophrenia are now well established. In addition, there has been increasing appreciation in recent years of the additional role of social cognitive impairment in driving functional outcomes and of the contributions of sensory-level dysfunction to higher-order impairments. At the neurochemical level, acute administration of N-methyl-d-aspartate receptor (NMDAR) antagonists reproduces the pattern of neurocognitive dysfunction associated with schizophrenia, encouraging the development of treatments targeted at both NMDAR and its interactome. At the local-circuit level, an auditory neurophysiological measure, mismatch negativity, has emerged both as a veridical index of NMDAR dysfunction and excitatory/inhibitory imbalance in schizophrenia and as a critical biomarker for early-stage translational drug development. Although no compounds have yet been approved for treatment of cognitive impairment associated with schizophrenia, several candidates are showing promise in early-phase testing.

Deviance Detection to Natural Stimuli in Population Responses of the Brainstem of Bats.

Deviance detection describes an increase of neural response strength caused by a stimulus with a low probability of occurrence. This ubiquitous phenomenon has been reported for humans and multiple other species, from subthalamic areas to the auditory cortex. Cortical deviance detection has been well characterized by a range of studies using a variety of different stimuli, from artificial to natural, with and without a behavioral relevance. This allowed the identification of a broad variety of regularity deviations that are detected by the cortex. Moreover, subcortical deviance detection has been studied with simple stimuli that are not meaningful to the subject. Here, we aim to bridge this gap by using noninvasively recorded auditory brainstem responses (ABRs) to investigate deviance detection at population level in the lower stations of the auditory system of a highly vocal species: the bat Carollia perspicillata (of either sex). Our present approach uses behaviorally relevant vocalization stimuli that are similar to the animals' natural soundscape. We show that deviance detection in ABRs is significantly stronger for echolocation pulses than for social communication calls or artificial sounds, indicating that subthalamic deviance detection depends on the behavioral meaning of a stimulus. Additionally, complex physical sound features like frequency- and amplitude modulation affected the strength of deviance detection in the ABR. In summary, our results suggest that the brain can detect different types of deviants already in the brainstem, showing that subthalamic brain structures exhibit more advanced forms of deviance detection than previously known.

Dependence of rhythmic activity and oddball effects in the rat cortex on the depth of sedation during dissociative anesthesia.

The reactions to novelty manifesting in mismatch negativity in the rat brain were studied. During dissociative anesthesia, mismatch negativity-like waves were recorded from the somatosensory cortex using an epidural 32-electrode array. Experimental animals: 7 wild-type Wistar rats and 3 transgenic rats. During high-dose anesthesia, deviant 1,500 Hz tones were presented randomly among many standard 1,000 Hz tones in the oddball paradigm. "Deviant minus standard_before_deviant" difference waves were calculated using both the classical method of Naatanen and method of cross-correlation of sub-averages. Both methods gave consistent results: an early phasic component of the N40 and later N100 to 200 (mismatch negativity itself) tonic component. The gamma and delta rhythms power and the frequency of down-states (suppressed activity periods) were assessed. In all rats, the amplitude of tonic component grew with increasing sedation depth. At the same time, a decrease in gamma power with a simultaneous increase in delta power and the frequency of down-states. The earlier phasic frontocentral component is associated with deviance detection, while the later tonic one over the auditory cortex reflects the orienting reaction. Under anesthesia, this slow mismatch negativity-like wave most likely reflects the tendency of the system to respond to any influences with delta waves, K-complexes and down-states, or produce them spontaneously.

Auditory prediction and prediction error responses evoked through a novel cascade roving paradigm: a human ECoG study.

Auditory sensory processing is assumed to occur in a hierarchical structure including the primary auditory cortex (A1), superior temporal gyrus, and frontal areas. These areas are postulated to generate predictions for incoming stimuli, creating an internal model of the surrounding environment. Previous studies on mismatch negativity have indicated the involvement of the superior temporal gyrus in this processing, whereas reports have been mixed regarding the contribution of the frontal cortex. We designed a novel auditory paradigm, the "cascade roving" paradigm, which incorporated complex structures (cascade sequences) into a roving paradigm. We analyzed electrocorticography data from six patients with refractory epilepsy who passively listened to this novel auditory paradigm and detected responses to deviants mainly in the superior temporal gyrus and inferior frontal gyrus. Notably, the inferior frontal gyrus exhibited broader distribution and sustained duration of deviant-elicited responses, seemingly differing in spatio-temporal characteristics from the prediction error responses observed in the superior temporal gyrus, compared with conventional oddball paradigms performed on the same participants. Moreover, we observed that the deviant responses were enhanced through stimulus repetition in the high-gamma range mainly in the superior temporal gyrus. These features of the novel paradigm may aid in our understanding of auditory predictive coding.

Tracking the habituation of the event-related EEG potential in automatic change detection using an auditory two-tone oddball paradigm.

The mismatch negativity and the P3a of the event-related EEG potential reflect the electrocortical response to a deviant stimulus in a series of stimuli. Although both components have been investigated in various paradigms, these paradigms usually incorporate many repetitions of the same deviant, thus leaving open whether both components vary as a function of the deviant's position in a series of deviant stimuli-i.e. whether they are subject to qualitative/quantitative habituation from one instantiation of a deviant to the next. This is so because the detection of mismatch negativity/P3a in the event-related EEG potential requires an averaging over dozens or hundreds of stimuli, i.e. over many instantiations of the deviant per participant. The present study addresses this research gap. We used a two-tone oddball paradigm implementing only a small number of (deviant) stimuli per participant, but applying it to a large number of participants (n > 230). Our data show that the mismatch negativity amplitude exhibits no decrease as a function of the deviant's position in a series of (standard and) deviant stimuli. Importantly, only after the very first deviant stimulus, a distinct P3a could be detected, indicative of an orienting reaction and an attention shift, and thus documenting a dissociation of mismatch negativity and P3a.

Assessing mismatch negativity (MMN) and P3b within-individual sensitivity - A comparison between the local-global paradigm and two specialized oddball sequences.

Mismatch negativity (MMN) and P3b are well known for their clinical utility. There exists no gold standard, however, for acquiring them as EEG markers of consciousness in clinical settings. This may explain why the within-individual sensitivity of MMN/P3b paradigms is often quite poor and why seemingly identical EEG markers can behave differently across Disorders of consciousness (DoC) studies. Here, we compare two traditional paradigms for MMN or P3b assessment with the recently more popular local-global paradigm that promises to assess MMN and P3b orthogonally within one oddball sequence. All three paradigms were administered to healthy participants (N = 15) with concurrent EEG. A clear MMN and local effect were found for 15/15 participants. The P3b and global effect were found for 14/15 and 13/15 participants, respectively. There were no systematic differences between the global effect and P3b. Indeed, P3b amplitude was highly correlated across paradigms. The local effect differed clearly from the MMN, however. It occurred earlier than MMN and was followed by a much more prominent P3a. The peak latencies and amplitudes were also not correlated across paradigms. Caution should therefore be exercised when comparing the local effect and MMN across studies. We conclude that the within-individual MMN sensitivity is adequate for both the local-global and a dedicated MMN paradigm. The within-individual sensitivity of P3b was lower than expected for both the local-global and a dedicated P3b paradigm, which may explain the often-low sensitivity of P3b paradigms in patients with DoC.

Predicting and coding sound into action translation in spinal cord injured people.

Motor activation in response to perception of action-related stimuli may depend on a resonance mechanism subserving action understanding. The extent to which this mechanism is innate or learned from sensorimotor experience is still unclear. Here, we recorded EEG while people with paraplegia or tetraplegia consequent to spinal cord injury (SCI) and healthy control participants were presented with action sounds produced by body parts (mouth, hands or feet) that were or were not affected by SCI. Non-action sounds were used as further control. We observed reduced brain activation in subjects affected by SCI at both pre- and post-stimulus latencies specifically for those actions whose effector was disconnected by the spinal lesion (i.e., hand sound for tetraplegia and leg sound for both paraplegia and tetraplegia). Correlation analyses showed that these modulations were functionally linked with the chronicity of the lesion, indicating that the longer the time the lesion- EEG data acquisition interval and/or the more the lesion occurred at a young age, the weaker was the cortical activity in response to these action sounds. Tellingly, source estimations confirmed that these modulations originated from a deficit in the motor resonance mechanism, by showing diminished activity in premotor (during prediction and perception) and near the primary motor (during perception) areas. Such dissociation along the cortical hierarchy is consistent with both previous reports in healthy subjects and with hierarchical predictive coding accounts. Overall, these data expand on the notion that sensorimotor experience maintains the cortical representations relevant to anticipate and perceive action-related stimuli.

Clarifying directional dependence among measures of early auditory processing and cognition in schizophrenia: leveraging Gaussian graphical models and Bayesian networks.

BACKGROUND: Research using latent variable models demonstrates that pre-attentive measures of early auditory processing (EAP) and cognition may initiate a cascading effect on daily functioning in schizophrenia. However, such models fail to account for relationships among individual measures of cognition and EAP, thereby limiting their utility. Hence, EAP and cognition may function as complementary and interacting measures of brain function rather than independent stages of information processing. Here, we apply a data-driven approach to identifying directional relationships among neurophysiologic and cognitive variables. METHODS: Using data from the Consortium on the Genetics of Schizophrenia 2, we estimated Gaussian Graphical Models and Bayesian networks to examine undirected and directed connections between measures of EAP, including mismatch negativity and P3a, and cognition in 663 outpatients with schizophrenia and 630 control participants. RESULTS: Chain structures emerged among EAP and attention/vigilance measures in schizophrenia and control groups. Concerning differences between the groups, object memory was an influential variable in schizophrenia upon which other cognitive domains depended, and working memory was an influential variable in controls. CONCLUSIONS: Measures of EAP and attention/vigilance are conditionally independent of other cognitive domains that were used in this study. Findings also revealed additional causal assumptions among measures of cognition that could help guide statistical control and ultimately help identify early-stage targets or surrogate endpoints in schizophrenia.

Effects of the cardiac cycle on auditory processing: A preregistered study on mismatch negativity.

The systolic and diastolic phases of the cardiac cycle are known to affect perception and cognition differently. Higher order processing tends to be facilitated at systole, whereas sensory processing of external stimuli tends to be impaired at systole compared to diastole. The current study aims to examine whether the cardiac cycle affects auditory deviance detection, as reflected in the mismatch negativity (MMN) of the event-related brain potential (ERP). We recorded the intensity deviance response to deviant tones (70 dB) presented among standard tones (60 or 80 dB, depending on blocks) and calculated the MMN by subtracting standard ERP waveforms from deviant ERP waveforms. We also assessed intensity-dependent N1 and P2 amplitude changes by subtracting ERPs elicited by soft standard tones (60 dB) from ERPs elicited by loud standard tones (80 dB). These subtraction methods were used to eliminate phase-locked cardiac-related electric artifacts that overlap auditory ERPs. The endogenous MMN was expected to be larger at systole, reflecting the facilitation of memory-based auditory deviance detection, whereas the exogenous N1 and P2 would be smaller at systole, reflecting impaired exteroceptive sensory processing. However, after the elimination of cardiac-related artifacts, there were no significant differences between systole and diastole in any ERP components. The intensity-dependent N1 and P2 amplitude changes were not obvious in either cardiac phase, probably because of the short interstimulus intervals. The lack of a cardiac phase effect on MMN amplitude suggests that preattentive auditory processing may not be affected by bodily signals from the heart.

Rare incompatible stimuli evoke visual mismatch negativity in a flanker task.

In the flanker task, the behavioral performance for incompatible stimuli is worse in the mostly compatible (rare) condition than in the equiprobable condition. Furthermore, incompatible stimuli evoke visual mismatch negativity (VMMN) when comparing the rare and equiprobable conditions. Compatible and incompatible stimuli differ in terms of their shape and type. This study aimed to examine whether VMMN evoked by rare incompatible stimuli were associated with the shape or type of the stimulus. In a modified version of the flanker task, stimuli were manipulated by two shapes (typical or peculiar) and two types (compatible or incompatible): typical compatible stimuli (< < < < < and > > > > >), typical incompatible stimuli (> > < > > and < < > < <), peculiar compatible stimuli (+ < < < + and + > > > +), and peculiar incompatible stimuli (+ > < > + and + < > < +). In the rare condition, typical incompatible, peculiar compatible, and peculiar incompatible stimuli were presented with a probability of 10%, whereas all the stimuli were presented equally in the equiprobable condition. Right posterior negativity from 200 to 250 ms was significantly more negative in the rare condition than in the equiprobable condition for typical and peculiar incompatible stimuli; however, this difference was not observed for peculiar compatible stimuli. VMMN was significantly more negative for typical and peculiar incompatible stimuli than for peculiar compatible stimuli, and was not significantly different between typical and peculiar incompatible stimuli. These findings suggest that VMMN for incompatible stimuli is associated with the type rather than the shape of the stimulus.

Cortical Generators and Connections Underlying Phoneme Perception: A Mismatch Negativity and P300 Investigation.

The cortical generators of the pure tone MMN and P300 have been thoroughly studied. Their nature and interaction with respect to phoneme perception, however, is poorly understood. Accordingly, the cortical sources and functional connections that underlie the MMN and P300 in relation to passive and active speech sound perception were identified. An inattentive and attentive phonemic oddball paradigm, eliciting a MMN and P300 respectively, were administered in 60 healthy adults during simultaneous high-density EEG recording. For both the MMN and P300, eLORETA source reconstruction was performed. The maximal cross-correlation was calculated between ROI-pairs to investigate inter-regional functional connectivity specific to passive and active deviant processing. MMN activation clusters were identified in the temporal (insula, superior temporal gyrus and temporal pole), frontal (rostral middle frontal and pars opercularis) and parietal (postcentral and supramarginal gyrus) cortex. Passive discrimination of deviant phonemes was aided by a network connecting right temporoparietal cortices to left frontal areas. For the P300, clusters with significantly higher activity were found in the frontal (caudal middle frontal and precentral), parietal (precuneus) and cingulate (posterior and isthmus) cortex. Significant intra- and interhemispheric connections between parietal, cingulate and occipital regions constituted the network governing active phonemic target detection. A predominantly bilateral network was found to underly both the MMN and P300. While passive phoneme discrimination is aided by a fronto-temporo-parietal network, active categorization calls on a network entailing fronto-parieto-cingulate cortices. Neural processing of phonemic contrasts, as reflected by the MMN and P300, does not appear to show pronounced lateralization to the language-dominant hemisphere.

Segregation and integration of sensory features by flexible temporal characteristics of independent neural representations.

Segregation and integration are two fundamental yet competing computations in cognition. For example, in serial speech processing, stable perception necessitates the sequential establishment of perceptual representations to remove irrelevant features for achieving invariance. Whereas multiple features need to combine to create a coherent percept. How to simultaneously achieve seemingly contradicted computations of segregation and integration in a serial process is unclear. To investigate their neural mechanisms, we used loudness and lexical tones as a research model and employed a novel multilevel oddball paradigm with Electroencephalogram (EEG) recordings to explore the dynamics of mismatch negativity (MMN) responses to their deviants. When two types of deviants were presented separately, distinct topographies of MMNs to loudness and tones were observed at different latencies (loudness earlier), supporting the sequential dynamics of independent representations for two features. When they changed simultaneously, the latency of responses to tones became shorter and aligned with that to loudness, while the topographies remained independent, yielding the combined MMN as a linear additive of single MMNs of loudness and tones. These results suggest that neural dynamics can be temporally synchronized to distinct sensory features and balance the computational demands of segregation and integration, grounding for invariance and feature binding in serial processing.

Spatiotemporal dynamics across visual cortical laminae support a predictive coding framework for interpreting mismatch responses.

Context modulates neocortical processing of sensory data. Unexpected visual stimuli elicit large responses in primary visual cortex (V1)-a phenomenon known as deviance detection (DD) at the neural level, or "mismatch negativity" (MMN) when measured with EEG. It remains unclear how visual DD/MMN signals emerge across cortical layers, in temporal relation to the onset of deviant stimuli, and with respect to brain oscillations. Here we employed a visual "oddball" sequence-a classic paradigm for studying aberrant DD/MMN in neuropsychiatric populations-and recorded local field potentials in V1 of awake mice with 16-channel multielectrode arrays. Multiunit activity and current source density profiles showed that although basic adaptation to redundant stimuli was present early (50 ms) in layer 4 responses, DD emerged later (150-230 ms) in supragranular layers (L2/3). This DD signal coincided with increased delta/theta (2-7 Hz) and high-gamma (70-80 Hz) oscillations in L2/3 and decreased beta oscillations (26-36 Hz) in L1. These results clarify the neocortical dynamics elicited during an oddball paradigm at a microcircuit level. They are consistent with a predictive coding framework, which posits that predictive suppression is present in cortical feed-back circuits, which synapse in L1, whereas "prediction errors" engage cortical feed-forward processing streams, which emanate from L2/3.

Brain plasticity and auditory spatial adaptation in patients with unilateral hearing loss.

The ability to localize sounds in patients with Unilateral Hearing Loss (UHL) is usually disrupted due to alteration in the integration of binaural cues. Nonetheless, some patients are able to compensate deficit using adaptive strategies. In this study, we explored the neural correlates underlying this adaptation. Twenty-one patients with UHL were separated into 3 groups using cluster analysis based on their binaural performance. The resulting clusters were referred to as better, moderate, and poorer performers cluster (BPC, MPC, and PPC). We measured the mismatch negativity (MMN) elicited by deviant sounds located at 10°, 20°, and 100° from a standard positioned at 50° ipsilateral to the deaf ear. The BPC exhibited significant MMN for all 3 deviants, similar to normal hearing (NH) subjects. In contrast, there was no significant MMN for 10° and 20° deviants for the PPC and for NH when one ear was plugged and muffed. Scalp distribution was maximal over central regions in BPC, while PPC showed more frontal MMN distribution. Thus, the BPC exhibited a contralateral activation pattern, similar to NH, while the PPC exhibited more symmetrical hemispheric activation. MMN can be used as a neural marker to reflect spatial adaptation in patients with UHL.

Longitudinal change in mismatch negativity (MMN) but not in gamma-band auditory steady-state response (ASSR) is associated with psychological difficulties in adolescence.

Adolescence is a critical period for psychological difficulties. Auditory mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are representative electrophysiological indices that mature during adolescence. However, the longitudinal association between MMN/ASSR and psychological difficulties among adolescents remains unclear. We measured MMN amplitude for duration and frequency changes and ASSR twice in a subsample (n = 67, mean age 13.4 and 16.1 years, respectively) from a large-scale population-based cohort. No significant longitudinal changes were observed in any of the electroencephalography indices. Changes in SDQ-TD were significantly associated with changes in duration MMN, but not frequency MMN and ASSR. Furthermore, the subgroup with higher SDQ-TD at follow-up showed a significant duration MMN decrease over time, whereas the subgroup with lower SDQ-TD did not. The results of our population neuroscience study suggest that insufficient changes in electroencephalography indices may have been because of the short follow-up period or non-monotonic change during adolescence, and indicated that the longitudinal association with psychological difficulties was specific to the duration MMN. These findings provide new insights that electrophysiological change may underlie the development of psychosocial difficulties emerging in adolescence.

Probing Beat Perception with Event-Related Potentials (ERPs) in Human Adults, Newborns, and Nonhuman Primates.

The aim of this chapter is to give an overview of how the perception of rhythmic temporal regularity such as a regular beat in music can be studied in human adults, human newborns, and nonhuman primates using event-related brain potentials (ERPs). First, we discuss different aspects of temporal structure in general, and musical rhythm in particular, and we discuss the possible mechanisms underlying the perception of regularity (e.g., a beat) in rhythm. Additionally, we highlight the importance of dissociating beat perception from the perception of other types of structure in rhythm, such as predictable sequences of temporal intervals, ordinal structure, and rhythmic grouping. In the second section of the chapter, we start with a discussion of auditory ERPs elicited by infrequent and frequent sounds: ERP responses to regularity violations, such as mismatch negativity (MMN), N2b, and P3, as well as early sensory responses to sounds, such as P1 and N1, have been shown to be instrumental in probing beat perception. Subsequently, we discuss how beat perception can be probed by comparing ERP responses to sounds in regular and irregular sequences, and by comparing ERP responses to sounds in different metrical positions in a rhythm, such as on and off the beat or on strong and weak beats. Finally, we will discuss previous research that has used the aforementioned ERPs and paradigms to study beat perception in human adults, human newborns, and nonhuman primates. In doing so, we consider the possible pitfalls and prospects of the technique, as well as future perspectives.

Mismatch Negativity and P300 in the Diagnosis and Prognostic Assessment of Coma and Other Disorders of Consciousness.

BACKGROUND: The objective of this study was to investigate the value of mismatch negativity (MMN) and P300 event-related potentials for discriminating the consciousness state and predicting improvement of consciousness at 6 months in patients with coma and other disorders of consciousness (DOC). METHODS: We performed MMN and P300 on 42 patients with DOC with a mean onset time of 40.21 ± 19.43 days. These patients with DOC were categorized into coma, unresponsive wakefulness syndrome (UWS), minimal consciousness minus (MCS-), and minimal consciousness plus (MCS +) groups according to neurobehavioral assessment and the Coma Recovery Scale-Revised score. The primary outcome was the improvement of consciousness at 6 months in patients with DOC. We assessed the efficacy of MMN and P300 in quantitatively predicting the prognosis at 6 months and the capability of MMN and P300 parameters to differentiate between DOC. RESULTS: At least one significant difference in either MMN or P300 parameters was displayed among the DOC groups, but not between the MCS- and MCS+ groups (significance level: 0.05). Both MMN and P300 amplitudes showed desirable predictive accuracy at 6 months, with areas under the curve (AUCs) of 0.859 and 0.856, respectively. The optimal thresholds for MMN and P300 amplitudes were 2.044 and 1.095 µV. However, the combined MMN-P300 amplitude showed better 6-month predictive accuracy (AUC 0.934, 95% confidence interval 0.860-1.000), with a sensitivity of 85% and a specificity of 90.9%. CONCLUSIONS: MMN and P300 may help discriminate among coma, UWS, and MCS, but not between patients with MCS- and patients with MCS+ . The MMN amplitude, P300 amplitude, and especially combined MMN-P300 amplitude at 6 months may be interesting predictors of consciousness improvement at 6 months in patients with DOC. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier ChiCTR2400083798.

Neural markers associated with improved tinnitus perception after tinnitus retraining therapy.

OBJECTIVE: Tinnitus retraining therapy (TRT) has been widely used in tinnitus management. However, its efficacy is often assessed through subjective methods. Here, we aimed to assess potential neural changes following TRT using mismatch negativity (MMN). DESIGN: Chronic tinnitus (>6 months) patients participated in a six-month TRT program. We collected tinnitus psychoacoustic features and gathered the tinnitus handicap inventory (THI) before and after TRT. We also used a multi-featured paradigm, including frequency, intensity, duration, location and silent gap deviants, to elicit MMN response before and after TRT. Data were analyzed retrospectively. STUDY SAMPLE: The study involved 26 chronic tinnitus patients. RESULTS: Post-TRT measurements showed that MMN amplitudes significantly increased for all deviant conditions (p ≤ .03). However, we did not find a significant difference in MMN latencies for all deviant conditions (p ≥ .13). The THI scores of the patients significantly decreased following the TRT program (p < 0.001). Our results reveal improved subjective tinnitus perception following the TRT program. CONCLUSION: These findings indicate that TRT might be a viable alternative in tinnitus management. The greater MMN amplitudes and improved subjective tinnitus perception raise the possibility that MMN can be a useful tool in tinnitus research and tinnitus patient follow-up.

Delirium is associated with loss of feedback cortical connectivity.

INTRODUCTION: Post-operative delirium (POD) is associated with increased morbidity and mortality but is bereft of treatments, largely due to our limited understanding of the underlying pathophysiology. We hypothesized that delirium reflects a disturbance in cortical connectivity that leads to altered predictions of the sensory environment. METHODS: High-density electroencephalogram recordings during an oddball auditory roving paradigm were collected from 131 patients. Dynamic causal modeling (DCM) analysis facilitated inference about the neuronal connectivity and inhibition-excitation dynamics underlying auditory-evoked responses. RESULTS: Mismatch negativity amplitudes were smaller in patients with POD. DCM showed that delirium was associated with decreased left-sided superior temporal gyrus (l-STG) to auditory cortex feedback connectivity. Feedback connectivity also negatively correlated with delirium severity and systemic inflammation. Increased inhibition of l-STG, with consequent decreases in feed-forward and feed-back connectivity, occurred for oddball tones during delirium. DISCUSSION: Delirium is associated with decreased feedback cortical connectivity, possibly resulting from increased intrinsic inhibitory tone. HIGHLIGHTS: Mismatch negativity amplitude was reduced in patients with delirium. Patients with postoperative delirium had increased feedforward connectivity before surgery. Feedback connectivity was diminished from left-side superior temporal gyrus to left primary auditory sensory area during delirium. Feedback connectivity inversely correlated with inflammation and delirium severity.

Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases.

The multiple demand (MD) system is a network of fronto-parietal brain regions active during the organization and control of diverse cognitive operations. It has been argued that this activation may be a nonspecific signal of task difficulty. However, here we provide convergent evidence for a causal role for the MD network in the "simple task" of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modeling (DCM), and frequency-resolved functional connectivity analyses of MRI and magnetoencephalography (MEG) from 75 mixed-sex human patients across four neurodegenerative syndromes [behavioral variant fronto-temporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), posterior cortical atrophy (PCA), and Alzheimer's disease mild cognitive impairment with positive amyloid imaging (ADMCI)] and 48 age-matched controls. We show that atrophy of any MD node is sufficient to impair auditory neurophysiological response to change in frequency, location, intensity, continuity, or duration. There was no similar association with atrophy of the cingulo-opercular, salience or language networks, or with global atrophy. MD regions displayed increased functional but decreased effective connectivity as a function of neurodegeneration, suggesting partially effective compensation. Overall, we show that damage to any of the nodes of the MD network is sufficient to impair top-down control of sensation, providing a common mechanism for impaired change detection across dementia syndromes.SIGNIFICANCE STATEMENT Previous evidence for fronto-parietal networks controlling perception is largely associative and may be confounded by task difficulty. Here, we use a preattentive measure of automatic auditory change detection [mismatch negativity (MMN) magnetoencephalography (MEG)] to show that neurodegeneration in any frontal or parietal multiple demand (MD) node impairs primary auditory cortex (A1) neurophysiological response to change through top-down mechanisms. This explains why the impaired ability to respond to change is a core feature across dementias, and other conditions driven by brain network dysfunction, such as schizophrenia. It validates theoretical frameworks in which neurodegenerating networks upregulate connectivity as partially effective compensation. The significance extends beyond network science and dementia, in its construct validation of dynamic causal modeling (DCM), and human confirmation of frequency-resolved analyses of animal neurodegeneration models.