Auditory hallucinations, top-down processing and language perception: a general population study.

BACKGROUND: Studies investigating the underlying mechanisms of hallucinations in patients with schizophrenia suggest that an imbalance in top-down expectations v. bottom-up processing underlies these errors in perception. This study evaluates this hypothesis by testing if individuals drawn from the general population who have had auditory hallucinations (AH) have more misperceptions in auditory language perception than those who have never hallucinated. METHODS: We used an online survey to determine the presence of hallucinations. Participants filled out the Questionnaire for Psychotic Experiences and participated in an auditory verbal recognition task to assess both correct perceptions (hits) and misperceptions (false alarms). A hearing test was performed to screen for hearing problems. RESULTS: A total of 5115 individuals from the general Dutch population participated in this study. Participants who reported AH in the week preceding the test had a higher false alarm rate in their auditory perception compared with those without such (recent) experiences. The more recent the AH were experienced, the more mistakes participants made. While the presence of verbal AH (AVH) was predictive for false alarm rate in auditory language perception, the presence of non-verbal or visual hallucinations were not. CONCLUSIONS: The presence of AVH predicted false alarm rate in auditory language perception, whereas the presence of non-verbal auditory or visual hallucinations was not, suggesting that enhanced top-down processing does not transfer across modalities. More false alarms were observed in participants who reported more recent AVHs. This is in line with models of enhanced influence of top-down expectations in persons who hallucinate.

Auditory hallucinations, not necessarily a hallmark of psychotic disorder.

Auditory hallucinations (AH) are often considered a sign of a psychotic disorder. This is promoted by the DSM-5 category of Other Specified Schizophrenia Spectrum And Other Psychotic Disorder (OSSSOPD), the diagnostic criteria for which are fulfilled with the sole presence of persistent AH, in the absence of any other psychotic symptoms. And yet, persistent AH are not synonymous with having a psychotic disorder, and should therefore not be uncritically treated as such. Many people who seek treatment for persistent AH have no other psychotic symptoms, have preserved reality-testing capacities, and will never develop a schizophrenia spectrum disorder. Instead, hallucinations may be the result of many different causes, including borderline personality disorder, post-traumatic stress disorder (PTSD), hearing loss, sleep disorders or brain lesions, and they may even occur outside the context of any demonstrable pathology. In such cases, the usage of the DSM-5 diagnosis of OSSSOPD would be incorrect, and it may prompt unwarranted treatment with antipsychotic medication. We therefore argue that a DSM-5 diagnosis of Schizophrenia Spectrum Disorder (or any other type of psychotic disorder) characterized by AH should require at least one more symptom listed under the A-criterion (i.e. delusions, disorganized speech, disorganized or catatonic behavior or negative symptoms). Adhering to these more stringent criteria may help to distinguish between individuals with persistent AH which are part of a psychotic disorder, for whom antipsychotic medication may be helpful, and individuals with AH in the absence of such a disorder who may benefit from other approaches (e.g. different pharmacological interventions, improving coping style, trauma-related therapy).

The impact of traumatic stress on Pavlovian biases.

BACKGROUND: Disturbances in Pavlovian valuation systems are reported to follow traumatic stress exposure. However, motivated decisions are also guided by instrumental mechanisms, but to date the effect of traumatic stress on these instrumental systems remain poorly investigated. Here, we examine whether a single episode of severe traumatic stress influences flexible instrumental decisions through an impact on a Pavlovian system. METHODS: Twenty-six survivors of the 2011 Norwegian terror attack and 30 matched control subjects performed an instrumental learning task in which Pavlovian and instrumental associations promoted congruent or conflicting responses. We used reinforcement learning models to infer how traumatic stress affected learning and decision-making. Based on the importance of dorsal anterior cingulate cortex (dACC) for cognitive control, we also investigated if individual concentrations of Glx (=glutamate + glutamine) in dACC predicted the Pavlovian bias of choice. RESULTS: Survivors of traumatic stress expressed a greater Pavlovian interference with instrumental action selection and had significantly lower levels of Glx in the dACC. Across subjects, the degree of Pavlovian interference was negatively associated with dACC Glx concentrations. CONCLUSIONS: Experiencing traumatic stress appears to render instrumental decisions less flexible by increasing the susceptibility to Pavlovian influences. An observed association between prefrontal glutamatergic levels and this Pavlovian bias provides novel insight into the neurochemical basis of decision-making, and suggests a mechanism by which traumatic stress can impair flexible instrumental behaviours.

Auditory verbal hallucinations: neuroimaging and treatment.

Auditory verbal hallucinations (AVH) are a frequently occurring phenomenon in the general population and are considered a psychotic symptom when presented in the context of a psychiatric disorder. Neuroimaging literature has shown that AVH are subserved by a variety of alterations in brain structure and function, which primarily concentrate around brain regions associated with the processing of auditory verbal stimuli and with executive control functions. However, the direction of association between AVH and brain function remains equivocal in certain research areas and needs to be carefully reviewed and interpreted. When AVH have significant impact on daily functioning, several efficacious treatments can be attempted such as antipsychotic medication, brain stimulation and cognitive-behavioural therapy. Interestingly, the neural correlates of these treatments largely overlap with brain regions involved in AVH. This suggests that the efficacy of treatment corresponds to a normalization of AVH-related brain activity. In this selected review, we give a compact yet comprehensive overview of the structural and functional neuroimaging literature on AVH, with a special focus on the neural correlates of efficacious treatment.

Lateralization of resting state networks and relationship to age and gender.

Brain lateralization is a widely studied topic, however there has been little work focused on lateralization of intrinsic networks (regions showing similar patterns of covariation among voxels) in the resting brain. In this study, we evaluate resting state network lateralization in an age and gender-balanced functional magnetic resonance imaging (fMRI) dataset comprising over 600 healthy subjects ranging in age from 12 to 71. After establishing sample-wide network lateralization properties, we continue with an investigation of age and gender effects on network lateralization. All data was gathered on the same scanner and preprocessed using an automated pipeline (Scott et al., 2011). Networks were extracted via group independent component analysis (gICA) (Calhoun et al., 2001). Twenty-eight resting state networks discussed in previous (Allen et al., 2011) work were re-analyzed with a focus on lateralization. We calculated homotopic voxelwise measures of laterality in addition to a global lateralization measure, called the laterality cofactor, for each network. As expected, many of the intrinsic brain networks were lateralized. For example, the visual network was strongly right lateralized, auditory network and default mode networks were mostly left lateralized. Attentional and frontal networks included nodes that were left lateralized and other nodes that were right lateralized. Age was strongly related to lateralization in multiple regions including sensorimotor network regions precentral gyrus, postcentral gyrus and supramarginal gyrus; and visual network regions lingual gyrus; attentional network regions inferior parietal lobule, superior parietal lobule and middle temporal gyrus; and frontal network regions including the inferior frontal gyrus. Gender showed significant effects mainly in two regions, including visual and frontal networks. For example, the inferior frontal gyrus was more right lateralized in males. Significant effects of age were found in sensorimotor and visual networks on the global measure. In summary, we report a large-sample of lateralization study that finds intrinsic functional brain networks to be highly lateralized, with regions that are strongly related to gender and age locally, and with age a strong factor in lateralization, and gender exhibiting a trend-level effect on global measures of laterality.

Genetic analyses of dopamine related genes in adult ADHD patients suggest an association with the DRD5-microsatellite repeat, but not with DRD4 or SLC6A3 VNTRs.

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder in children and adults. Recent meta-analyses have indicated an association between genes involved in dopaminergic signaling and childhood ADHD, but little is known about their possible role in adult ADHD. In this study of adults with ADHD, we evaluated the three most commonly studied ADHD candidate genetic polymorphisms; the dopamine receptor D4 (DRD4) exon 3 VNTR repeat, a microsatellite repeat 18.5 kb upstream of the DRD5 locus and the 3'UTR dopamine transporter SLC6A3 (DAT 1) VNTR. We examined 358 clinically diagnosed adult Norwegian ADHD patients (51% males) and 340 ethnically matched controls. We found a nominally significant overall association with adult ADHD for the DRD5 microsatellite marker (P = 0.04), and a trend toward increased risk associated with the 148-bp allele consistent with recent meta-analyses. The strongest overall association (P = 0.02) and increased risk for the 148-bp allele [odds ratio (OR) = 1.27 (95% CI: 1.00-1.61)] were seen in the inattentive and combined inattentive/hyperactive group as previously reported for childhood ADHD. No association was found for the DRD4 or SLC6A3 polymorphisms in this patient sample. In conclusion, our results among adults with a clinical diagnosis of ADHD support an association between ADHD and the DRD5 locus, but not the DRD4 or SLC6A3 loci. It is possible that the latter polymorphisms are associated with a transient form of ADHD with better long-term clinical outcome.

Cognitive influences on human autonomic nervous system function.

Recent studies of human autonomic nervous system function have challenged the traditional view that the parasympathetic and sympathetic branches have opposite effects. In addition, studies of autonomic activity that accompanies attention, orienting and learning have demonstrated that the autonomic nervous system is not simply a 'non-cognitive' and automatic part of brain function. The autonomic and central nervous systems are intimately related, and new research is beginning to link brain function with autonomic function in a dynamic way.

Increased spatial granularity of left brain activation and unique age/gender signatures: a 4D frequency domain approach to cerebral lateralization at rest.

Cerebral lateralization is a well-studied topic. However, most of the research to date in functional magnetic resonance imaging (fMRI) has been carried out on hemodynamic fluctuations of voxels, networks, or regions of interest (ROIs). For example, cerebral differences can be revealed by comparing the temporal activation of an ROI in one hemisphere with the corresponding homotopic region in the other hemisphere. While this approach can reveal significant information about cerebral organization, it does not provide information about the full spatiotemporal organization of the hemispheres. The cerebral differences revealed in literature suggest that hemispheres have different spatiotemporal organization in the resting state. In this study, we evaluate cerebral lateralization in the 4D spatiotemporal frequency domain to compare the hemispheres in the context of general activation patterns at different spatial and temporal scales. We use a gender-balanced resting fMRI dataset comprising over 600 healthy subjects ranging in age from 12 to 71, that have previously been studied with a network specific voxel-wise and global analysis of lateralization (Agcaoglu, et al. NeuroImage, 2014). Our analysis elucidates significant differences in the spatiotemporal organization of brain activity between hemispheres, and generally more spatiotemporal fluctuation in the left hemisphere especially in the high spatial frequency bands, and more power in the right hemisphere in the low and middle spatial frequencies. Importantly, the identified effects are not visible in the context of a typical assessment of voxelwise, regional, or even global laterality, thus our study highlights the value of 4D spatiotemporal frequency domain analyses as a complementary and powerful tool for studying brain function.

Suicidality in schizophrenia spectrum disorders: the relationship to hallucinations and persecutory delusions.

BACKGROUND: Assessment of suicide risk is crucial in schizophrenia and results concerning risk contributed by hallucinations and persecutory delusions are inconsistent. We aimed to determine factors associated with suicidal ideation and plans at the time of acute admission in patients suffering from schizophrenia spectrum disorders. METHODS: One hundred and twenty-four patients older than 18 years admitted to an acute psychiatric ward due to psychosis were consecutively included. Predictors of suicidal ideation and suicide plans at the time of admission were examined with multinominal logistic regression and structural equation modelling (SEM). The study design was pragmatic, thus entailing a clinically relevant representation. RESULTS: Depression Odds Ratio (OR) 12.9, Drug use OR 4.07, Hallucinations OR 2.55 and Negative symptoms OR 0.88 significantly predicted Suicidal ideation. Suspiciousness/ Persecution did not. Only Depression and Hallucinations significantly predicted Suicide plans. In the SEM-model Anxiety, Depression and Hopelessness connected Suspiciousness/Persecution, Hallucinations and Lack of insight with Suicidal ideation and Suicide plans. CONCLUSIONS: The study contributes to an increasing evidence base supporting an association between hallucinations and suicide risk. We want to emphasise the importance of treating depression and hallucinations in psychotic disorders, reducing hopelessness while working with insight and reducing drug abuse in order to lower suicide risk. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/NCT00932529.

Hemispheric asymmetry in schizophrenia: a "dual deficits" model.

BACKGROUND: The aim was 1) to investigate left hemisphere functional integrity for auditory language processing in schizophrenic patients; and 2) to investigate the interaction between brain laterality and attentional processing by having subjects shift attention to the left or right ear. METHODS: The subjects were 33 schizophrenic inpatients, and 33 healthy comparison subjects with the same age, handedness, and gender distribution as the patient subjects. All subjects were tested with dichotic listening (DL) to consonant-vowel syllables, which is a measure of lateralized temporal lobe language processing. The subjects were tested under three different attentional conditions: a non-forced attention condition, attention focused to the right ear stimulus, and attention focused to the left ear stimulus. RESULTS: The main findings were 1) an absence of the expected right ear advantage in the schizophrenic group during the non-forced attention condition; and 2) a failure to modify DL performance through shifting of attention to either the right or left ear. The comparison group showed a right ear advantage during the non-forced and forced-right attention conditions (increased right ear advantage during the forced-right condition), and a left ear advantage during the forced-left attention condition. There were no significant effects of handedness. CONCLUSIONS: This pattern of results may indicate a "dual deficit" involving both automatic and controlled processing deficits in schizophrenia.

Dichotic listening during auditory hallucinations in patients with schizophrenia.

OBJECTIVE: Auditory hallucinations are a serious problem for a large subgroup of psychotic patients who do not respond optimally to neuroleptic medication. It has been hypothesized that hearing imaginary voices involves the same physiological processes as those involved in hearing real voices, but this hypothesis has not been conclusively confirmed. METHOD: In this study a consonant-vowel version of the Dichotic Listening Test was used to assess the functional integration of the left hemisphere in hallucinating and nonhallucinating psychotic patients. The test was administered under three conditions: a nonforced attention condition, a condition in which attention was forced to the left ear, and one in which attention was forced to the right ear. RESULTS: The nonhallucinating patients showed the normal right ear advantage, which indicates a left hemisphere superiority in the processing of linguistic stimuli. In contrast, the hallucinating patients showed no ear advantage. Neither group was able to modify its performance when instructed to attend to either the left or the right ear. A subgroup of patients was tested in both hallucinating and nonhallucinating states, but the ear asymmetry was not noticeably different between these states. CONCLUSIONS: The results suggest that auditory hallucinations are associated with abnormalities in left hemisphere functioning and that these abnormalities might not be limited to the time of the auditory hallucinations. It is hypothesized that a relatively enduring left hemisphere abnormality may leave some patients at risk for auditory hallucinations.

Dichotic-listening performance and intracarotid injections of amobarbital in children and adolescents. Preoperative and postoperative comparisons.

BACKGROUND: Dichotic listening (DL) to consonant-vowel syllables is frequently used in clinical and experimental studies of brain laterality. However, the paradigm of consonant-vowel syllables has not been thoroughly validated through a comparison with injections of amobarbital sodium (Amytal). OBJECTIVE: To validate the DL test for hemisphere dominance preoperatively vs postoperatively with the results from intracarotid injections of amobarbital (i.e., the Wada test) in epileptic children and adolescents. DESIGN AND MAIN OUTCOME MEASURES: Patients were tested with DL preoperatively and at 6-month follow-up. Correct reports in the DL tests were entered in a stepwise discriminant analysis for calculation of correct classification of hemisphere dominance with the results from the injections of amobarbital as the grouping variable. Correct reports from the right and left ears on the consonant-vowel DL test were compared preoperatively and postoperatively, separated for the subjects with regard to language dominance in the left and right hemispheres. SETTING: The Department of Pediatrics, Ostra Hospital, University of Göteborg, Göteborg, Sweden. PATIENTS: Thirteen children and adolescents between the ages of 10 and 19 years, who were surgically treated for resistant epilepsy, were included in the study. The operated area corresponded with morphological changes and functional dysfunctions according to findings from computed tomography, magnetic resonance imaging, single photon emission computed tomography, and electroencephalography. RESULTS: The results of the Wada tests revealed that 10 subjects had left hemisphere language dominance, with 3 subjects having right hemisphere language dominance. All 3 subjects with right hemisphere language dominance showed a left ear advantage on the DL test preoperatively and postoperatively, with 8 and 7 of the 10 subjects with left hemisphere dominance showing a right ear advantage, preoperatively and postoperatively, respectively. However, according to discriminant analysis, knowledge of the DL performance led to a correct classification according to the Wada test results in 12 (92%) of the 13 subjects. CONCLUSIONS: A quantitative classification procedure like discriminant analysis may be more sensitive when predicting hemisphere speech dominance from DL data than a qualitative procedure based on the ear advantage dichotomy. The ear advantage dichotomy may actually introduce arbitrary left-right categories that do not correspond to the actual clustering of the data.

Dichotic listening in 126 left-handed children: ear advantages, familial sinistrality and sex differences.

In the present study we report data on dichotic listening (DL) performance in 126 left-handed children. Four specific questions were addressed: (1) What is the percentage of left-handers in a large sample of children in Sweden? (2) What is the distribution of children showing a right ear (REA), left ear (LEA), and no ear (NEA) advantage in DL? (3) What is the relationship between ear advantage and familial sinistrality in children? (4) Are there sex differences among left-handed children, and if so, are these differences also reflected in DL performance? The results showed that the left-handers constituted 8.1% of the total sample of the screened subjects. The DL results showed 65.0% REA, 25.4% LEA, and 9.6% NEA. Of the subjects, 45.2% had left-handed relatives. Overall, there were more boys than girls in the sample (65.1% vs 34.9%). It is concluded that the present data match the sodium-Amytal data on left-handed adults with about 2/3 of a left-handed population with left hemisphere language dominance.

Immune and autoimmune diseases in dyslexic children.

One hundred and five dyslexic and 105 control children were compared for frequency of immune diseases, autoimmune diseases, and non-right-handedness in the light of the Geschwind-Behan (1982) "testosterone hypothesis". The results showed significantly more immune- and autoimmune-diseases int he dyslexic group. There were no differences between the groups in the frequency of non-right-handedness. There were no interactions with gender, although there were more non-right-handed boys than girls in the total sample. Mothers of children who were dyslexic experienced significantly more negative life-events during pregnancy, they also experienced the pregnancy as more difficult, and they had more spontaneous abortions. In conclusion, the results support some aspects of the "testosterone hypothesis", but they also point to a more complex pattern of interaction between the factors that still remain unanswered.

Left-handedness and old age: do left-handers die earlier?

Data are presented on the prevalence of current left-handedness and prior left-handedness (switched) in 2787 subjects from 21 to 101 years of age. In addition, data on sex differences, familial sinistrality, hand posture when writing, and education were recorded. Two hypotheses were tested. The elimination hypothesis states that reduced frequency of left-handers in old age is due to reduced longevity. The modification hypothesis states that differences in the number of left-handers between older and younger persons are due to changing patterns of social norms. The results showed a decreasing prevalence of left-handedness across the age span, with 15.22% in the youngest group (21-30 years), but only 1.67% in subjects older than 80 years. There was however a corresponding increase in the number of subjects who had switched hand for writing, 2.69% in the youngest group to 6.75% in subjects 80 years and above. This supports the modification hypothesis and questions the elimination hypothesis. However, the mean percent score was still lower in subjects above compared to below age 40 after correction for hand switching. Thus, although changes in social norms towards left-handers seem to be the most likely explanation, we have not empirically disproved the elimination hypothesis.

Normal lateralization for handedness and ear advantage in a verbal dichotic listening task in women with congenital adrenal hyperplasia (CAH).

Functional cerebral asymmetry was studied in 22 women, 17-34 years old, with prenatal virilization due to congenital adrenal hyperplasia (CAH) (21-hydroxylase deficiency) and 22 matched, healthy controls. The theory of an androgen influence on cerebral lateralization has been supported by the observation of sex differences in cognitive performance, anatomical cerebral differences between the sexes and atypical patterns of functional asymmetry in certain anomalous hormonal states. The result of the present study did however not show a significantly different pattern of functional asymmetry for women with CAH and prenatal exposure to high levels of androgens. No significant differences with the controls were found for the Finger Tapping Test (FTT), Edinburgh Handedness Inventory (EHI) or Dichotic Listening (Consonant-Vowel) Test (DL). The CAH group included four non-right-handers (18%) vs two (9%) in the control group. As sex differences generally are small, the present result, may have been influenced by the limited size of the sample.

Left and right-handed dyslexic boys: an empirical test of some assumptions of the Geschwind-Behan hypothesis.

Twenty-six dyslexic boys (13 left-handers and 13 right-handers) were tested for hemispheric asymmetry with dichotic listening (DL) and a visual half-field test (VHF). The purpose of the study was an empirical test of the Geschwind-Behan [Proc. natn. Acad. Sci. USA 79, 5097-5100, 1982] hypothesis of a difference in hemispheric asymmetry between left- and right-handed dyslexic boys. Following Geschwind and Behan, left-handedness and dyslexia are caused by a common factor affecting the development of the left hemisphere in utero which results in a right hemisphere dominance. As a consequence, handedness but not language is shifted to the right hemisphere. We therefore predicted that left-handed dyslexics should be superior to right-handed dyslexics on visuospatial tasks, but perform similar to right-handers on verbal tasks. The results revealed a significant right ear advantage (REA) in both groups during a dichotic listening test to verbal stimuli. The left-handed group was however superior to the right-handed group in recognition of visuo-spatial stimuli presented in the left half-field in a visual half-field test. It is concluded that the results provide some, although weak, support for the Geschwind-Behan hypothesis.

Pathological left-handedness revisited: dichotic listening in children with left vs right congenital hemiplegia.

Thirty-one children with right (n = 18) and left (n = 13) congenital hemiplegia were compared for incidence of hand- and foot-preference, eye-dominance, and familial sinistrality. In addition, they were tested with dichotic listening for correct reports of consonant-vowel syllables. The two groups of children were closely matched on IQ and sensory functioning. Children with mental retardation, or epileptic seizures were not included. The results showed that 89% of the left hemisphere impaired (LHI) children were left-handed, all of them preferred the left foot, and 72% were left eye-dominant. In the right hemisphere impaired (RHI) group, everyone (100%) preferred the right hand and foot, and 62% were right eye dominant. The dichotic listening results showed a significant right ear advantage (REA) in the RHI-group, and a significant left ear advantage (LEA) in the LHI-group. The results are discussed in the framework of pathological handedness and shifts in hemisphere control of language in children with early brain injury. It is argued that the homogeneous samples, except for the site of lesion, provides an interesting possibility to compare cognitive effects of left and right hemisphere impairment in children.

Brain activation during dichotic presentations of consonant-vowel and musical instrument stimuli: a 15O-PET study.

Dichotic listening means that two different stimuli are presented at the same time, one in each ear. This technique is frequently used in experimental and clinical studies as a measure of hemispheric specialization. The primary aim of the present study was to record regional changes in the distribution of cerebral blood flow (CBF) with the 15O-PET technique to dichotically presented consonant-vowel (CV) and musical instrument stimuli, in order to test the basic assumption of differential hemispheric involvement when stimuli presented to one ear dominate over stimuli presented in the other ear. All stimuli were 380 ms in duration with a 1000 ms interstimulus interval, and were presented in blocks of either CV-syllable or musical instrument pairs. Twelve normal healthy subjects had to press a button whenever they detected a CV-syllable or a musical instrument target in a stream of CV- and musical instrument distractor stimuli. The targets appeared equally often in the right and left ear channel. The CV-syllable and musical instrument targets activated bilateral areas in the superior temporal gyri. However, there were significant interactions with regard to asymmetry of the magnitude of peak activation in the significant activation clusters. The CV-syllables resulted in greater neural activation in the left temporal lobe while the musical instruments resulted in greater neural activation in the right temporal lobe. Within-subjects correlations between magnitude of dichotic listening and CBF asymmetry were, however, non-significant. The changes in neural activation were closely mimicked by the performance data which showed a right ear superiority in response accuracy for the CV-syllables, and a left ear superiority for the musical instruments. In addition to the temporal lobe activations, there were activation tendencies in the left inferior frontal lobe, right dorsolateral prefrontal cortex, left occipital lobe, and cerebellum.