Auditory verbal hallucinations (AVH) in schizophrenia are typically characterized by rich emotional content. Despite the prominent role of emotion in regulating normal perception, the neural interface between emotion-processing regions such as the amygdala and auditory regions involved in perception remains relatively unexplored in AVH. Here, we studied brain metabolism using FDG-PET in 9 remitted patients with schizophrenia that previously reported severe AVH during an acute psychotic episode and 8 matched healthy controls. Participants were scanned twice: (1) at rest and (2) during the perception of aversive auditory stimuli mimicking the content of AVH. Compared to controls, remitted patients showed an exaggerated response to the AVH-like stimuli in limbic and paralimbic regions, including the left amygdala. Furthermore, patients displayed abnormally strong connections between the amygdala and auditory regions of the cortex and thalamus, along with abnormally weak connections between the amygdala and medial prefrontal cortex. These results suggest that abnormal modulation of the auditory cortex by limbic-thalamic structures might be involved in the pathophysiology of AVH and may potentially account for the emotional features that characterize hallucinatory percepts in schizophrenia.
References
[1]
Allen P, Laroi F, McGuire PK, Aleman A (2008) The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations. Neurosci Biobehav Rev 32: 175–191.
[2]
Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am? J? Psychiatry 160: 13–23.
[3]
Calder AJ, Lawrence AD, Young AW (2001) Neuropsychology of fear and loathing. Nat Rev Neurosci 2: 352–363.
[4]
Baxter MG, Murray EA (2002) The amygdala and reward. Nat Rev Neurosci 3: 563–573.
[5]
Fletcher PC, Frith CD (2009) Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nat Rev Neurosci 10: 48–58.
[6]
Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E (2008) The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am? J? Psychiatry 165: 1015–1023.
[7]
Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, et al. (2000) Meta-analysis of regional brain volumes in schizophrenia. Am? J? Psychiatry 157: 16–25.
[8]
Benes FM (2010) Amygdalocortical circuitry in schizophrenia: from circuits to molecules. Neuropsychopharmacology 35: 239–257.
[9]
Schneider F, Weiss U, Kessler C, Salloum JB, Posse S, et al. (1998) Differential amygdala activation in schizophrenia during sadness. Schizophr Res 34: 133–142.
[10]
Holt DJ, Kunkel L, Weiss AP, Goff DC, Wright CI, et al. (2006) Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia. Schizophr Res 82: 153–162.
[11]
Fernandez-Egea E, Parellada E, Lomena F, Falcon C, Pavia J, et al. (2010) 18FDG PET study of amygdalar activity during facial emotion recognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci 260: 69–76.
[12]
Taylor SF, Liberzon I, Decker LR, Koeppe RA (2002) A functional anatomic study of emotion in schizophrenia. Schizophr Res 58: 159–172.
[13]
Anderson AK, Phelps EA (2001) Lesions of the human amygdala impair enhanced perception of emotionally salient events. Nature 411: 305–309.
[14]
Sanjuan J, Lull JJ, Aguilar EJ, Marti-Bonmati L, Moratal D, et al. (2007) Emotional words induce enhanced brain activity in schizophrenic patients with auditory hallucinations. Psychiatry Res 154: 21–29.
[15]
Ait Bentaleb L, Stip E, Mendrek A, Mensour B, Beauregard M (2006) [Effects of listening to previously hallucinated words by schizophrenia patients in remission: a functional magnetic resonance imaging study of six cases]. Encephale 32: 27–40.
[16]
Holt DJ, Weiss AP, Rauch SL, Wright CI, Zalesak M, et al. (2005) Sustained activation of the hippocampus in response to fearful faces in schizophrenia. Biol Psychiatry 57: 1011–1019.
[17]
Taylor SF, Phan KL, Britton JC, Liberzon I (2005) Neural response to emotional salience in schizophrenia. Neuropsychopharmacology 30: 984–995.
[18]
Salgado-Pineda P, Fakra E, Delaveau P, Hariri AR, Blin O (2010) Differential patterns of initial and sustained responses in amygdala and cortical regions to emotional stimuli in schizophrenia patients and healthy participants. J? Psychiatry Neurosci 35: 41–48.
[19]
Horga G, Parellada E, Lomena F, Fernandez-Egea E, Mane A, et al. (2011) Differential brain glucose metabolic patterns in antipsychotic-naive first-episode schizophrenia with and without auditory verbal hallucinations. J? Psychiatry Neurosci 36: 312–321.
[20]
Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13: 261–276.
[21]
Andreasen NC, Flaum M, Arndt S (1992) The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 49: 615–623.
[22]
Haddock G, McCarron J, Tarrier N, Faragher EB (1999) Scales to measure dimensions of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS). Psychol Med 29: 879–889.
[23]
Weber WA, Schwaiger M, Avril N (2000) Quantitative assessment of tumor metabolism using FDG-PET imaging. Nucl Med Biol 27: 683–687.
[24]
Grunder G (2009) "Absolute" or "relative": choosing the right outcome measure in neuroimaging. Neuroimage 45: 258–259.
[25]
Lee DS, Kang H, Kim H, Park H, Oh JS, et al. (2008) Metabolic connectivity by interregional correlation analysis using statistical parametric mapping (SPM) and FDG brain PET; methodological development and patterns of metabolic connectivity in adults. Eur? J? Nucl Med Mol Imaging 35: 1681–1691.
[26]
Morbelli S, Drzezga A, Perneczky R, Frisoni GB, Caroli A, et al. (2012) Resting metabolic connectivity in prodromal Alzheimer's disease. A European Alzheimer Disease Consortium (EADC) project. Neurobiol Aging 33: 2533–2550.
[27]
Taylor PA, Gohel S, Di X, Walter M, Biswal BB (2012) Functional covariance networks: obtaining resting-state networks from intersubject variability. Brain Connect 2: 203–217.
[28]
Zhang Z, Liao W, Zuo XN, Wang Z, Yuan C, et al. (2011) Resting-state brain organization revealed by functional covariance networks. PLoS One 6: e28817.
[29]
Di X, Biswal BB (2012) Metabolic brain covariant networks as revealed by FDG-PET with reference to resting-state fMRI networks. Brain Connect 2: 275–283.
[30]
Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, et al. (2000) Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 10: 120–131.
[31]
Anticevic A, Repovs G, Barch DM (2012) Emotion effects on attention, amygdala activation, and functional connectivity in schizophrenia. Schizophr Bull 38: 967–980.
[32]
Lacadie CM, Fulbright RK, Rajeevan N, Constable RT, Papademetris X (2008) More accurate Talairach coordinates for neuroimaging using non-linear registration. Neuroimage 42: 717–725.
[33]
Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am? J? Psychiatry 148: 1474–1486.
[34]
Anticevic A, Van Snellenberg JX, Cohen RE, Repovs G, Dowd EC, et al. (2012) Amygdala recruitment in schizophrenia in response to aversive emotional material: a meta-analysis of neuroimaging studies. Schizophr Bull 38: 608–621.
[35]
Diederen KM, Neggers SF, Daalman K, Blom JD, Goekoop R, et al. (2010) Deactivation of the parahippocampal gyrus preceding auditory hallucinations in schizophrenia. Am? J? Psychiatry 167: 427–435.
[36]
Kumar S, von Kriegstein K, Friston K, Griffiths TD (2012) Features versus feelings: dissociable representations of the acoustic features and valence of aversive sounds. J? Neurosci 32: 14184–14192.
[37]
Gusnard DA, Akbudak E, Shulman GL, Raichle ME (2001) Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proc Natl Acad Sci? U? S? A 98: 4259–4264.
[38]
Ochsner KN, Knierim K, Ludlow DH, Hanelin J, Ramachandran T, et al. (2004) Reflecting upon feelings: an fMRI study of neural systems supporting the attribution of emotion to self and other. J? Cogn Neurosci 16: 1746–1772.
[39]
Ochsner KN, Bunge SA, Gross JJ, Gabrieli JD (2002) Rethinking feelings: an FMRI study of the cognitive regulation of emotion. J? Cogn Neurosci 14: 1215–1229.
Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC (2009) Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry 66: 811–822.
[42]
Pomarol-Clotet E, Canales-Rodriguez EJ, Salvador R, Sarro S, Gomar JJ, et al. (2010) Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging. Mol Psychiatry 15: 823–830.
[43]
Waters F, Allen P, Aleman A, Fernyhough C, Woodward TS, et al. (2012) Auditory hallucinations in schizophrenia and nonschizophrenia populations: a review and integrated model of cognitive mechanisms. Schizophr Bull 38: 683–693.
[44]
Leaver AM, Renier L, Chevillet MA, Morgan S, Kim HJ, et al. (2011) Dysregulation of limbic and auditory networks in tinnitus. Neuron 69: 33–43.
[45]
Maudoux A, Lefebvre P, Cabay JE, Demertzi A, Vanhaudenhuyse A, et al. (2012) Auditory resting-state network connectivity in tinnitus: a functional MRI study. PLoS One 7: e36222.
[46]
Rauschecker JP, Leaver AM, Muhlau M (2010) Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron 66: 819–826.