Abstract

Introduction

Auditory verbal hallucinations (AVHs), defined as perceptions or subjective experiences of “hearing voices” without corresponding external auditory stimulation, occur with a high frequency of up to 60% to 80% in patients with schizophrenia (SZ) (1). Reflecting a diverse phenomenological experience, AVHs can involve words, sentences, or conversations (with varied clarity, loudness, and spatial locations) spoken as commands, comments, insults, or encouragements by familiar or unfamiliar single and/or multiple voices (in first, second, or third person) (2).

Although the causes of AVHs are still unclear, improved understanding of the neural basis of AVHs has been forthcoming from functional magnetic resonance imaging (fMRI) studies which have shown elevated activation of brain regions associated with auditory stimulus processing, speech generation, and speech perception during the experience of active hallucinations (vs. silent rest) (3–6). Paradoxically, although in sensory cortices hyper-excitable neuronal states are typically associated with enhanced exogenous induced processes (7–10), AVHs have been associated with reduced neuronal activation of the auditory cortex in response to external auditory stimulation (11). These opposing findings in hallucinating patients of increased activation of the auditory cortex in the absence of external stimulation and reduced activation of the auditory cortex in response to externally presented speech and non-speech sounds have been interpreted as evidence for competition between internally generated and externally originating neural activity in the auditory cortex for the attentional resources of the hallucinating patient (11). Also evidenced in SZ patients who are prone to AVHs (vs. patients who have never hallucinated), diminished neural responsiveness to external auditory stimulation is believed to affect the functional cost of an auditory cortex that is thought to be tonically “tuned on” and “tuned in” to the internal channels broadcasting hallucinating stimuli, with the preferential endogenous processing of AVHs resulting in the “saturation” of neuronal resources and resulting in limited capacity for the exogenous processing of external auditory stimuli (12, 13).

Further evidence that the auditory cortex in hallucinating patients is overly sensitive to activation arising from internal processing, while being less responsive to external stimulation, comes from electrophysiological studies assessing cortical responsiveness to auditory stimuli with electroencephalographically (EEG)-derived event-related potential (ERP) components that have been shown to be generated in the auditory cortex and have been extensively used to document profound early auditory information processing (EAIP) deficits in SZ (14). Patients with SZ have been found to be impaired with respect to two aspects of EAIP: inhibiting intrinsic responses to redundant stimuli (to prevent sensory overload), and facilitating/detecting potentially salient stimuli (for extended higher-order processing and response) (15). These elementary pre-attentive auditory input deficits in SZ are reflected in two candidate ERP endophenotypes, one of which includes P50 sensory gating as a measure of inhibitory failure. This inhibitory deficit is indexed in SZ both by minimal suppression of P50 (an early central-maximum positive scalp component elicited at ~50 ms in response to the second stimulus [S₂] of click pairs [S₁-S₂]), and by a diminished S₁ P50 amplitude (16). A second ERP endophenotype of EAIP dysfunction in SZ, mismatch negativity (MMN), is a frontal maximum negative scalp component at ~150 to 200 ms which indexes automatic acoustic deviance detection and, in SZ, exhibits a reduced amplitude in response to changes in physical or abstract features in auditory oddball paradigms (17).

Although both of these ERP-indexed elementary sensory processes (auditory gating and auditory charge detection) have been consistently shown to be abnormal in SZ, our findings indicated a significant worsening of these brain sensory functions in patients who hallucinate (trait positive) as: (1) increasing negative affective content of AVHs was inversely related with S₁ P50 amplitude (18); (2) SZ hallucinators (vs. non-hallucinators) exhibited smaller MMNs to changes in pure tone stimuli (19), with MMN reduction being more evident with increasing trait ratings of hallucinatory activity (20); and (3) SZ hallucinators (vs. healthy controls) showed smaller MMNs to pure tone and speech deviant stimuli (21). Furthermore, in SZ patients who are prone to hallucinate, we observed diminished involuntary attentional orienting to speech stimuli (evidenced by a reduction in a later [~300 ms] frontocentral positive [P3_a] scalp component), suggesting an impairment in the ability of human speech deviations to capture attention (22). Together with findings of reduced amplitude of the N1 component of the auditory ERP during hallucinating states (23), observed ERP deficits in sensory registration (N1), sensory inhibition (P50), sensory discrimination (MMN), and stimulus selection (P3_a) within the auditory modality are consistent with the “saturation” hypothesis of AVHs. The resulting competitive outcome favoring resource allocation to the processing of internal auditory signals may in part explain the profound behavioral performance deficits of SZ patients during auditory discrimination tasks (24).

AVHs are associated with high levels of distress likely related to idiosyncratic beliefs or cognitive appraisals involving control, power, voice identity, authority, and consequences of not complying with the voices (25–27). Despite adequate dosages of antipsychotic drugs, AVHs are drug resistant in ~25% of SZ patients, and become chronic, causing an impaired quality of life (28) and diminished cognitive capacity, with the latter playing a key role in functional outcome (29). Cognitive behavioral therapy (CBT) has been suggested as a complement to pharmacotherapy for targeting psychosis in treatment resistant cases (30–32). Reviews (33–37) and multiple meta-analyses (38, 39, 40–42) on the effectiveness of specialized cognitive behavioral therapy for psychosis (CBTp), developed, and recommended as an adjunctive treatment for decreasing distress in patients with persistent AVHs (43, 44), found a modest but significant positive impact on positive symptoms, negative symptoms, and general psychopathology. The proposed mechanism of change resulting from CBTv is through changes in beliefs about voices as well as enhancing coping skills (33).

In contrast to CBTp, which is aimed at a broad array of symptoms, administering tailored therapies for specific symptoms and using a recommended symptoms specific approach such as CBT for voices (CBTv) (34, 40) has shown effectiveness in individual and group sessions. In three randomized controlled group CBTv trials, improvements have been found not only in positive and general symptoms, but also in self-esteem, effective coping strategies and social functioning, as well as reductions in voice frequency and perceived voice power (35, 45–49).

Methods

Treatment Design

Following a parallel group design, 14 (8 males) of the 25 patients were randomly assigned to receive CBTv for 5 months in addition to their usual treatment (CBTv group) and eleven (7 males) were randomly assigned to continue their treatment as usual (TAU group). The recruitment and creation of groups involved: (i) a patient referral through hospital psychiatrist to the study team; (ii) the introduction of the study requirements and involvement by the study team and consent from participants; (iii) completion of screening session to ensure patients met the study requirements; and (iv) random assignment to treatment groups. In the CBTv group, patients received CBTv for 5 to 6 months, while patients in the TAU were followed for the same time period. Following completion, TAU patients then completed 5 months of CBTv treatment (Figure 1). The two laboratory test sessions, one at baseline and one at follow-up, included electrophysiological recordings, assessment of psychiatric symptoms, and completion of questionnaires relating to AVHs.

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Figure 1

Flow chart of treatment design.

Of the fourteen patients assigned to the CBTv condition, thirteen patients (8 males) completed all assessments at baseline and follow-up and provided usable EEG data. Of the eleven patients recruited in TAU group, nine (5 males) completed all assessments at baseline and follow-up and provided usable EEG data. Of the nine patients who completed the TAU group, six completed all assessment at baseline, follow-up, and post-CBTv, and provided usable EEG data. All patients who completed the study continued with their regular medication and psychosocial interventions throughout the study period. The main reasons for attrition or exclusions from the study were: (i) consent withdrawal; (ii) incomplete or unusable EEG data at one or both time points (e.g. noisy EEG data, less than 40 clean EEG epochs per deviant stimulus, and missing EEG channels; (iv) medication change; and (v) onset of medical illness.

ERP Procedures

ERPs were recorded with a cap embedded with Ag⁺/Ag⁺Cl⁻ electrodes (EasyCap, Herrching-Brieibrunn, Germany) positioned on 32 (see Figure 2) according to the 10–10 system (85). An electrode on the nose served as reference and a ground electrode was positioned at the AF_z electrode site. Electrodes were placed above and below the right eye to record vertical electrooculographic (VEOG) activity. Electrical recordings were carried out using a Brain Vision QuickAmp^® (Brain Products, GmbH, Munich, Germany) amplifier and Brain Vision Recorder^® (Brain Products GmbH, Munich, Germany) software. Electrical activity was sampled at 500 Hz, with amplifier bandpass filters set at 0.1 to 100.0 Hz. Electrode impedances were kept below 5 kΩ.

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Figure 2

Baseline (raw) grand-averaged ERP waveforms elicited by the standard and five deviant stimuli for all participants (N=24), shown across scalp sites and highlighted at F_z with respect to both raw (unsubtracted) and subtracted (deviant minus standard) difference waveforms.

Off-line analysis was performed with Brain Vision Analyzer^® software (Brain Products, GmbH, Munich, Germany). For each stimulus, electrical epochs of 500 ms duration (beginning 100 ms prior to stimulus onset) were digitally filtered (0.1–20 Hz) (86), ocular (87) and baseline corrected (relative to the pre-stimulus segment), and only epochs with EEG voltages ± 75 µV were used for final ERP averages, which were constructed separately for the standard and each deviant stimulus type at each electrode site. Waveforms for the low and high pitch deviants, those for the low- and high-intensity deviants, and those for the right and left location, were averaged together. The mean number of epochs for MMN averages was not significantly different between deviants, nor were there differences in epoch numbers (for each deviant) across test sessions or between treatment groups.

MMNs elicited by frequency (fMMN), duration (dMMN), intensity (iMMN), gap (gMMN), and location (lMMN) deviants were analyzed with difference waveforms, which were derived by digital point-by-point subtraction of the standard stimulus values from those elicited by each of the deviant stimuli. Grand average waveforms, raw and subtracted, are displayed in Figure 2. MMN amplitude was defined as the most negative peak (± 5 ms) between 120 and 250 ms at the frontal electrodes (F₃, F_z, F₄), the sites exhibiting maximum MMN amplitudes. Amplitude of the N1 component (peak negativity between 90 and 120 ms) elicited by the standard stimulus was also measured (from F_z) as an index of sensory registration, which is typically reduced in chronic SZ (88).

Results

Of the fourteen patients assigned to CBTv, thirteen (8 males) completed all assessments at baseline and follow-up and provided usable EEG recordings. Of the eleven patients assigned to TAU, ten (6 males) completed all assessments at baseline and follow-up and provided usable EEG recordings. Thus, the attrition rate was 8%, with onset of medical illness (one patient) and unusable EEG data (one patient) accounting for patient-drops. During their subsequent participation in CBTv, only six of the ten patients in the TAU group completed all assessments at baseline (i.e., some data as from their follow-up session post TAU) and at follow-up and provided usable EEG recordings. Patent-drops were due to either change in medication (one patient), or unusable EEG (two patients). The final CBTv and TAU groups were similar in age, gender, year of education, duration of illness, PANSS positive, PANSS negative, PANNS total and PSYRATS total scores (Table 1).

Table 1

Demographic and clinical measures for treatment groups.

Demographics	CBTv group (n = 13; 7 males)		TAU group (n = 10; 6 males)
	Mean ± SD Baseline	Mean ± SD Follow-up	Mean ± SD Baseline	Mean ± SD Follow-up
Age (years)	41.77 ± 14.69		47.8 ± 11.81
Education (years)	4.62 ± 1.33		5.5 ± 1.18
Duration of illness (years)	16.1 ± 11.64		21.78 ± 9.60
PSYRATS total	25.15 ± 5.38	22.53 ± 6.21	27.5 ± 4.62	27.89 ± 4.76
PANSS
Positive Scale	15.62 ± 3.31	16.2 ± 4.41	15.6 ± 3.53	16.17 ± 5.94
Negative Scale	15.77 ± 4.78	16.2 ± 4.59	15.5 ± 4.17	13.7 ± 5.28
General	33.31 ± 13.71	30.3 ± 6.17	31.3 ± 6.43	31.67 ± 7.71

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PSYRATS, The Auditory Hallucinations subscale from the Psychotic Symptom Rating Scale; PANSS, Positive and Negative Syndrome Scale.

Follow-up for the PANSS measures included missing data (3 missing cases from the CBTv group and 4 missing cases from the TAU only group).

CBTv Effects on Clinical/AVH Symptoms

Between-Group Analyses

The CBTv group did not differ from the TAU group with respect to changes in PANSS positive, negative or general symptoms (Table 1). Similarly, no group differences were observed with respect to changes in the frequency and quality of AVH symptoms assessed with PSYRATS ratings (Table 1).

For the BAVQ-R, significant time effects were observed for two of the subscale scores, omnipotence (F = 7.36, df = 1/21, p = 0.013) and resistance behavior (F = 4.37, df = 1/21, p = 0.049). Planned comparisons found these reductions in omnipotence (p = 0.014) and increases in resistance behavior (p = 0.015) ratings between baseline and follow-up to be limited to the CBTv group (Figure 3). Analysis of VAAS rating failed to yield any significant group, time or interaction effects but ratings scores on both the CHOICE severity (F = 8.08, df = 1/21, p = 0.01) and CHOICE satisfaction (F = 12.16, df = 1/21, p = 0.002) dimensions showed significant time effects, with planned comparisons showing significant changes in severity (p = 0.003) and satisfaction (p = 0.008) only in the CBTv group (Figure 3).

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Figure 3

Mean (± SE) rating scores for BAV-Q, VAAS, and CHOICE instruments administered to patients in CBTv and TAU conditions at pre- (baseline) and post-treatment.

Combined Group Analyses

Changes from pre- to post-CBTv were not observed for PANSS or VAAS ratings but significant reductions were shown for total PSYRATS (p=0.035), BAVQ-R omnipotence (p=0.0013) and CHOICE severity (p=0.009) rating scores (Figure 4).

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Figure 4

Mean (± SE) pre- (baseline) and post-treatment rating scores for BAV-Q, VAAS, and CHOICE instruments administered to all patients (N=22) completing CBTv.

CBTv Effects on MMN/N100 Amplitude/Latency

Between-Group Analyses

Analysis of frontal amplitudes did not reveal any significant group, treatment, or time effects for MMN elicited by intensity, duration, gap or location deviants. A significant treatment x time interaction (F = 15.78, df = 1/40, p = 0.001) was shown for the pitch deviant, with planned comparisons revealing significant increases in pMMN amplitudes in the CBTv group at follow-up compared to baseline (p = 0.001) as well as greater pMMN amplitudes in CBTv group compared to TAU group p = 0.043) at follow-up (Figure 5). Analysis of MMN latency yielded a significant treatment x time interaction for the gap deviant (F = 4.41, df = 1/25, p = 0.049) with planned comparisons showing a reduced (earlier) gMMN latency (Figure 6) in the CBTv group (p = 0.019) at follow-up (M = 148.68 ms, SE ± 6.86) compared to baseline (M = 164.02 ms, SE ± 6.92). Neither the amplitude nor latency of N100 were affected by treatment.

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Figure 5

Grand-averaged subtracted pitch deviant waveforms at frontal (F₃, Fz, F₄) sites recorded pre- (baseline) and post-treatment in patients assigned to CBTv and TAU conditions.

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Figure 6

Grand-averaged subtracted gap deviant waveforms at mid-frontal site (Fz) recorded pre- (baseline) and post-treatment in patients assigned to CBTv and TAU conditions.

Combined Group Analyses

A significant time effect was observed only for the pitch deviant (F = 14.68, df = 1/18, p = 0.001), with pMMN amplitudes showing an increase at follow-up compared to baseline (Figure 7). Analyses of the duration deviant yielded a significant time x electrode interaction (F = 9.12, df = 1/36, p = 0.002), with comparisons of left frontal (F3) amplitude showing a greater dMMN amplitude (p = 0.029) at follow-up compared to baseline (Figure 7). For MMN latency, analysis showed a significant time effect for the duration deviant (F = 6.71, df = 1/18, p = 0.018), with dMMN exhibiting a shorter latency (M = 153.01 ms, SE ± 7.11) at follow-up compared to baseline (M = 166.46 ms, SE ± 6.03) latency (Figure 7). No treatment effects were observed for N100 amplitude or latency.

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Figure 7

Grand-averaged subtracted pitch (A) and duration (B) deviant waveforms at frontal (F₃, F_z, F₄) sites recorded pre- (baseline) and post-treatment in all patients (N=22) completing CBTv.

CBTv Effects on Source Localized CD

Between-Group Analyses

For the pMMN, analysis of localized CD yielded a significant region effect (F = 33.53, df = 1/21, p = 0.001), with CD of the sAC being greater than CD of the pAC. A significant treatment x time x hemisphere interaction was also evidenced (F = 11.62, df = 1/21, p = 0.008), with planned comparisons finding increases (p = 0.008) in CD in the left hemisphere of the CBTv group at follow-up compared to baseline (Figure 8).

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Figure 8

Mean (± SE) current density values (ln[Å/m²]) of the left and right hemisphere of the auditory cortex (pAC and sAC combined) in patients assigned to CBTv and TAU conditions.

Combined Group Analyses

Analysis of CD associated with the pMMN showed significant (F = 17.85, df = 1/18, p = 0.001) region effect, with CD in the sAC being greater than CD in the pAC. In significant time (F = 5.38, df = 1/18, p = 0.032) and time x hemisphere interaction effects (F = 8.27, df = 1/18, p = 0.010), planned comparisons showed significant overall increases (p = 0.002) in CD of the left auditory cortex in the CBTv group at follow-up compared to baseline (Figure 9).

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Figure 9

Mean (± SE) current density values (ln[Å/m²]) of the left and right hemisphere of the primary and secondary auditory cortex in all patients (N=22) completing CBTv.

Relationships Between Symptoms and MMN/CD

In the initial CBTv group, changes in the pMMN amplitude (from baseline to follow-up) were positively correlated with changes in the resistance emotion subscale of the BAVQ-R (r = 0.64, p = 0.029), and negatively correlated with the total (r = −0.76, p = 0.002) and both the activation (r = −0.82, p = 0.001) and acceptance (r = −0.70, p = 0.008) scores of the VAAS (Figure 10). Treatment-induced changes in symptoms were found to be related to treatment-induced changes in CD of the auditory cortex but only in the left pAC. In this region of the auditory cortex, CD changes were positively correlated with changes in the benevolence (r = 0.63, p = 0.021), resistance emotion (r = 0.55, p = 0.05) and engagement behavior subscale scores (r = 0.54, p = 0.04) of the BAVQ-R, and negatively correlated with changes of the total VASS(r = −0.68, p = 0.01) score (Figure 11).

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Figure 10

Scatterplots showing relationships between pitch MMN amplitude change and BAV-Q and VAAS ratings change in the initial group receiving CBTv.

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Figure 11

Scatterplots showing the relationships between changes in pitch MMN current density (CSD) in the left primary auditory cortex (pAC) and BAVQ-R and VAAS rating changes in the initial group receiving CBTv.

Discussion

This pilot study shows changes in EAIP during a pure tone auditory oddball paradigm in a sample of patients with SZ and persistent AVHs, attributable to the effects of CBTv. Compared to patients receiving TAU in the initial analyses, the patients who underwent CBTv showed significantly greater increases in auditory deviance detection as evidenced in enhanced MMN response to pitch deviants and faster (earlier latency) MMN responses to auditory gap deviants at treatment follow-up. These changes occurred independently of general psychiatric symptoms (PANSS) and changes in sensory registration (N100). The patients that received therapy also showed significant increases in activation (CD) of the left auditory cortex during the processing of auditory pitch deviants. Although CBTv did not affect self-reports of the frequency or quality of AVHs (PYSRATS), or the severity of psychotic symptoms (PANSS), it improved patients' perceptions and behavioral response to AVHs (BAVQ-R), and CBTv was thought by patients to be associated with better outcome (CHOICE) than TAU. Even more interestingly, these clinical changes together with self-reported improvements in patient beliefs about AVHs (VAAS) at CBTv follow-up were associated with increases in MMN response and left auditory cortex activation to pitch deviants.

Targeting the cognitive appraisals, perceptions, and beliefs concerning the nature of psychotic symptoms, both individual CBT (41) and group CBT in SZ (102) have been effective in alleviating positive psychotic symptoms as a whole (i.e. hallucinations and delusions) but, as with our own negative findings, the efficacy of CBT interventions specific for hallucinations has been mixed in regards to reductions in the frequency and severity of these symptoms (103, 104). Similar mixed findings in SZ have been reported in CBT trials with added ACC and ATT techniques (105). Our augmented CBTv did however affect AVH-related beliefs and behavioral reactions to hallucinations, shown by reductions in BAVQ-R Omnipotence and BAVQ-R Resistance Behavior scores, which may in part have accounted for patients' favorable outcome perception (CHOICE) with this therapy.

Reductions in conviction of beliefs about the power/authority (omnipotence) of voices and compliance to voices have been observed in previous group CBTp trials (105–107) and are clinically important considering that our patients' hallucinations have failed to respond to effective antipsychotic drugs. Employing specialized interventions like CBTv to target beliefs about voice omnipotence, particularly with respect to commanding aspects of the voices, which have been linked to a range of dangerous behaviors (aggression, violence, self-harm, and suicide), is a therapeutically relevant goal as voice omnipotence predicts compliance to hallucinations, and reductions in these beliefs about voices are associated with reduced cognitive functioning given their negative relationship with exogenous attentional processes (26, 108–110).

Consistent with our hypotheses that dampening the impact of internal voice processing with CBTv would result in the enhanced sensory processing of external auditory stimuli, improvements in EAIP with therapy were evidenced by larger pMMN and shorter gMMN responses in SZ patients with persistent AVHs. Rarely examined with other deviant types, abnormal deviance detection in SZ has been most frequently documented with pitch and duration, and occasionally with intensity changes in simple sound stimuli (17, 111, 112). While pMMN is thought to be sensitive to illness duration/disease progression, the dMMN behaves more as a trait index and as a valid endophenotype reflecting greater vulnerability to illness (17). Although not consistently observed, attenuated pMMN, dMMN, and iMMN have been observed in our laboratory in hallucinating (vs. non-hallucinating) SZ patients and have been correlated with hallucinatory severity ratings (19–22, 113, 114).

Possibly reflecting contributions from bilateral prefrontal cortices, the auditory MMN response to both simple sound and speech deviants is mainly dependent on synaptic plasticity mediated by glutamatergic N-methyl-d-aspartate (NMDA) receptors in the auditory cortex (115–117). Although also shown with the detection of duration deviants in our combined group analysis, the more reliable improvements in deviance detection with CBTv were observed in response to the pitch deviant, with pMMN being shown to be increased in both sets of analyses along with pitch CD in auditory cortices. Not always associated with auditory hallucinatory experiences, SZ is associated with deficits in the perception of a broad range of auditory features, including pitch discrimination as measured in tone-matching tasks (118). Dependent on the low-level acoustic features or type of complex naturalistic sound, the neural representation and processing of acoustic stimuli is confined to different regions within the human auditory system. The neural mechanisms underlying pitch perception are still largely debated but are assumed to involve a hierarchy of pitch processing steps, starting in the subcortical structures and terminating at the cortical level, where perceived pitch (variations) is most likely encoded (119). Certain areas of the auditory cortex are specifically sensitive to pitch, and although the locations are still another debate (120), previous functional neuroimaging has identified pitch-coding regions, including anterior-lateral pAC (on Heschl's gyrus [HG]) and adjacent sAC processing areas (on the superior temporal gyrus [STG]) (121), and extending to the planum temporale during the passive influences of infrequent pitch changes (122, 123). Increased pMMN (and dMMN) amplitudes with CBTv in patients experiencing persistent AVHs is consistent with brain volumetric studies showing negative relationships between left hemisphere HG/STG volume and both hallucination severity (122, 123) and MMN amplitude in SZ patients (124).

Changes in the appraisal of and response to AVHs with CBTv were associated with enhanced pMMN amplitudes and selective increases in pitch CD in the left pAC, and are consistent with the current status of AVHs in that they implicate speech perception areas in the left temporal lobe, improving perception of and attention to external sounds. These relationships between changes in auditory neural responsiveness and AVH symptom ratings are in line not only with structural studies showing the left pAC gray matter volume reduction in SZ to be associated with AVH severity (122, 123, 125), but also with functional neuroimaging studies confirming a “paradoxical” brain activation in relation to AVHs—the left pAC evidencing increased activation (during silent rest) in the absence of an external stimulus, and decreased activation in the presence of an external auditory stimulus (11). Although the specific brain mechanisms underlying these alterations are not understood, it is reasonable to speculate that they may be mediated by changes in glutamate neurotransmission. Aberrant glutamate levels in temporal and prefrontal cortical areas are found in SZ with frequent and severe hallucinations (126, 127) and glutamate receptor mediated synaptic plasticity in the pAC, as indexed by MMN alteration, is compromised in patients with SZ and particularly in patients with AVHs. Although not necessarily affecting tonic glutamate levels, changes in MMN responsiveness to pitch deviance with CBTv and adjunctive ATT and ACC techniques may indicate an increased ability to adequately modify synaptic plasticity in response to auditory (glutamate) neurotransmission resulting from external auditory stimulation.

The co-occurrence of altered ratings of beliefs/responses to AVHs together with changes in neural response (pMMN) to auditory deviance, which was shown to be statistically correlated with changes in beliefs, behavioral/emotional (BAVQ-R) and coping response (VAAS) to hallucinations, may be tentatively explained by the influence of CBTv on a common underlying NMDA receptor-mediated process—prediction error signaling. In a predictive coding framework, predictive coding is viewed as a hierarchical information processing model which posits interactions between lower-order (bottom-up) perceptual signals and higher-order cognitive processes in a dynamic, interactive fashion to generate predictions about the environment and compare incoming stimuli with these predictions (128, 129). Within this model, neural responses to stimuli that match predictions are suppressed, while stimuli that are unexpected, violating these predictions, trigger a mismatch “prediction error” signal, which signals that updating of expectations is required to accommodate the discrepant stimuli (130–132). It has been proposed that in hallucinating patients, excess aberrant spontaneous activation of the auditory sensory cortex may be confused by the brain with activity typically seen with external auditory stimulation, leading to erroneous expectations of a perceptual event (predictive coding failure) with the brain inferring externally located voices which in turn leads to a false (AVH) perception (129, 133, 134). Predictive tone signaling has been observed at the earliest levels of auditory cortical hierarchy—in the pAC (135). The MMN is hypothesized to reflect a prediction error signal (e.g. the properties of the deviant stimulus do not match the predictive model formed by the train of preceding standards, thus the model must be updated in order to improve predictive accuracy) (136), which is attenuated during NMDA receptor antagonist treatment with ketamine (137–139) and can be used to examine abnormalities in predictive coding. In a roving standard MMN paradigm, which allows for optimal evaluation of prediction errors (140), MMN deficits in SZ have reflected attenuated prediction error signaling (141). This is particularly pronounced in hallucinating (v. non-hallucinating) patients and consistent with a predictive coding account of hallucinations in SZ (142).

Hallucinatory experiences are associated with hyper-activation of the primary and secondary sensory areas, possibly due to dysregulation related to frontal lobe hypo-activation. Different brain mechanisms appear to underlie the clinical effects of pharmacotherapy and psychotherapy (143, 144). It has been argued that psychotherapeutic approaches such as CBT may exert their affects by gaining control of the function of particular circuits, such as changes in appraisal, control of attention, modulation of interceptive processes, and may involve key nodes, such as anterior cingulate and medial prefrontal areas (involved in error detection and conflict monitoring), dorsolateral prefrontal cortex areas (involved in cognitive control/working memory), and insula (interceptive sensitivity) (105). We can also speculate that different psychotherapeutical strategies may have different brain effects within a circuit. In our augmented treatment protocol, CBT and AAC focused on controlling the emotional response to hallucinations might be based on decreasing endogenous brain activity in the temporal/limbic areas, while ATT focused on auditory perceptual processes might be based on increasing externally induced brain activity in these same regions. Although not directly comparable with ATT, targeted cognitive training (TCT) of the auditory system in SZ patients has been shown to drive plasticity in cortical activation patterns related to both sensory representations as well as higher order cognitive processes (145, 146). In patients with SZ, TCT has not only produced significant improvements in auditory perception and learning, which was predicted by MMN (147), but also increases in verbal learning and reductions in AVHs (148, 149). Improvements in higher order auditory processing gained through TCT in SZ are dependent on the severity of basic auditory deficits (150). Given that the MMN response to deviant sounds has also been shown to have a direct mediating effect on cognition and functional outcome in SZ patients (151), future research may want to examine the effects of pairing CBTv with TCT aimed at improving auditory discrimination as a potential optimal strategy that would benefit both AVH symptoms and cognitive and psychosocial functioning.

Limitations

This study has several limitations. Regarding adherence to CBTv, a fidelity/treatment response scale was not used, and future research would benefit from audiotaping (with consent) and using a fidelity measure and independently trained raters. Although the results are relatively consistent across the two sets of analyses, they require replication in a larger sample. Patients were randomized to CBTv and TAU vs TAU only conditions but blindness was not a component of the study design and should be an aim in future work. Concurrent antipsychotic treatment may have influenced the results, but both groups of patients were receiving similar treatments. In order to reduce Type 1 error rates our source analysis with eLORETA was limited to two ROI, and additional studies are required to examine CBTv effects on non-auditory brain regions, especially frontal areas which are thought to contribute to MMN generation during deviance detection and to interact with auditory cortices in producing AVHs. External auditory stimulation for MMN generation was limited to pure tone deviants and additional studies need to examine CBTv effects on the processing of complex natural sounds including MMN response to speech deviants, which appear to be particularly sensitive to EAIP dysfunction in patients with SZ (21, 152) and as with MMN to response to pure tone deviants are reflective of NMDA receptor-mediated neurotransmission in auditory cortices (117). Functional neuroimaging has shown that the neural encoding of natural sounds (e.g., speech, voice) entails the formation of multiple representations of sound spectrograms with different degrees of spectral and temporal resolution (152–154). Combining the superior temporal and spatial resolution of EEG and fMRI techniques, respectively, to image neural activity during resting-state (absence of external auditory stimulation) and in response to behaviorally relevant, real-world sound stimuli would be an optimal strategy for achieving a more complete picture of brain mechanisms involved in AVH responsiveness to CBTv in SZ patients (155–160).

Finally, we assessed responsivity to external auditory stimulation on the neural level and there is a need to incorporate behavioral assessments (e.g., tone-matching and dichotic listening tasks) in order to examine performance changes associated with auditory processing. Optimally, these would be complemented with tests assessing changes in cognitive and functional outcome with CBTv.

Conclusion

In conclusion, we have shown for the first time significant changes in MMN responsiveness to external auditory deviants in SZ patients undergoing cognitive therapy for persistent auditory hallucinations. Correlated with improvements in patient's response to hallucinations, these neural findings improve our understanding of how psychotherapy may benefit patients with AVH, possibly by shifts in perceptual processing from internal distressing auditory (voices) stimulation to potentially relevant changes in external auditory stimuli. As these present observations were captured in a relatively small test sample, confirmation of these observations in larger studies integrating biomarkers like MMN to elucidate treatment effect mechanisms will help to increase our understanding of and ability to personalize psychotherapeutic approaches such as CBTv (153, 154).

Data Availability Statement

The datasets generated for this study are available on request to the corresponding author.

Ethics Statement

The studies involving human participants were reviewed and approved by Dominique Bourget, Acting Chair, University of Ottawa Institute of Mental Health Research REB. The patients/participants provided their written informed consent to participate in this study.

Author Contributions

VK and NW were responsible for the conceptualization of the study, NW lead the CBT for patients and was assisted by DS. Recruitment was the responsibility of AL and coordination, testing, and data analysis were performed by HB, DS, SS, and AB. Manuscript was prepared by VK and figures and tables were prepared by SS.

Funding

This work was supported by a grant from the University of Ottawa Medical Research Fund to NW, VK, and AL.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References