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Online Discussions

Updated 4 December 2008 E-mail discussion
Printable version

Live Discussion: Synchronized Neural Oscillations in the Pathophysiology of Schizophrenia

Peter Uhlhaas

Kevin Spencer

View article

On 16 December 2008, at 12:00 noon (US Eastern time), Peter Uhlhaas of the Max-Planck Institute for Brain Research, Frankfurt, and Kevin Spencer of Harvard University will lead us in a discussion of the possible role of synchronized, oscillatory activity in the pathophysiology of schizophrenia. Not only will they assess the current evidence, they will take a critical look at the methods and interpretation of data. The online chat will also allow attendees to discuss the possible mechanisms underlying these proposed abnormalities and possible neurodevelopmental antecedents.

Our live discussions always go best when the wheels are "greased" with some preliminary comments, so please read and comment on the backgrounder below and the review article by Uhlhaas and colleagues. (Our special thanks to Schizophrenia Bulletin, the Maryland Psychiatric Research Center, and Oxford Press for allowing us to post this free article!)

Uhlhaas PJ, Haenschel C, Nikolić D, Singer W. The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophr Bull. 2008 Sep;34(5):927-43. Abstract

Watch a two-part explication of the discussion topic: Part 1 by Kevin Spencer and Part 2 by Peter Uhlhaas, and then please read and comment on the backgrounder and the review article by Uhlhaas and colleagues.

View Transcript of Live Discussion — Posted 6 January 2009

View Comments By:
Didier Pinault — Posted 13 December 2008
Georg Winterer — Posted 10 January 2011

Background Text
by Kevin Spencer and Peter Uhlhaas

Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. By now, there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neural responses are associated with synchronized oscillatory activity in the θ-, α-, β-, and γ-band, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to its role during normal brain functioning, neural synchrony may be altered in major neuropsychiatric disorders, such as schizophrenia. Thus, there is good evidence on the alterations in high-frequency oscillations in schizophrenia as well as preliminary evidence for impairments in θ- and α-band activity. Accordingly, altered neural synchrony may represent the functional correlate of dysconnectivity in cortical networks that underlie the characteristic fragmentation of mind and behavior in schizophrenia. Impaired neural synchrony may also be linked directly to altered neurotransmitter systems in schizophrenia as much is already known about the underlying neurotransmitter systems involved in the generation of oscillations. Manipulation of neurotransmitter systems in in-vitro experiments, for example, allows a direct test of the involvement of specific receptors systems in the generation of abnormal rhythmic activity that provide critical tests for pathophysiological mechanisms in schizophrenia.

Although the initial evidence for a role of neural synchrony in the pathophysiology of schizophrenia seems promising, we nonetheless consider a number of issues critical for the progress in this field. Some provisional questions for discussion will be the following:

1. What is the evidence for impaired neural synchrony in schizophrenia? Are specific frequencies affected? Is it a generalized impairment? Is it specific to schizophrenia?

2. Which methods have yielded the best results? Do we need standardization of methods?

3. What are the possible mechanisms underlying impaired neural synchrony in schizophrenia?

4. How can neural synchrony account for the neurodevelopmental profile of schizophrenia?

Singer and colleagues proposed the “temporal correlation hypothesis” (e.g., Singer, 1999), that precise (ms) synchronization of neural firing mediates the “binding” of information coded by separate neurons into coherent representations. This neuronal synchronization could be mediated by oscillatory activity across different frequency bands:

Delta (δ): 1-4 Hz
Theta (θ): 4-8 Hz
Alpha (α): 8-13 Hz
Beta (β): 13-30 Hz
Gamma (γ): 30-100 Hz

(It should be noted that the exact definitions of frequency bands vary among researchers.)

It has been proposed that fast oscillations (β, γ) may synchronize neurons within local circuits, while slower oscillations (δ, θ, α) may coordinate the synchronization of neurons across brain regions, and also gate high-frequency oscillations (e.g., Sirota et al., 2008).

To analyze oscillatory synchronization, it is necessary to decompose the EEG in the frequency domain. Simple methods are filtering and frequency analysis within a fixed epoch, but these are limited in time and frequency resolution. Better methods perform a joint time/frequency analysis, such as with wavelets or a windowed Fast Fourier Transform (FFT). There are also methods to analyze oscillatory synchrony between brain regions, which typically involve the application of wavelets or windowed FFTs to obtain power or phase coherence between the signals measured at separate sensors. (For review, see Roach and Mathalon, 2008).

Two basic types of oscillations have been defined: 1) evoked oscillations, which are phase-locked to a stimulus (or other reference time point); and 2) induced oscillations, which are not strongly phase-locked to the stimulus, but are jittered in latency across trials. The measures of oscillations that are commonly used complement these definitions: evoked power measures the power of oscillations that are phase-locked to the stimulus, and are computed from the average of single trials (the average ERP). Total power includes both evoked and induced oscillations, and is measured in the average of single-trial power spectra. The phase-locking factor (or value) measures the degree to which an oscillation is phase-locked to a stimulus, and is independent of power.

Oscillation Abnormalities in Schizophrenia
A variety of abnormalities of fast oscillations have been observed in schizophrenia. A partial list includes the following:

  • Auditory steady-state response (ASSR).
  • Early visual-evoked γ.
  • Early auditory-evoked γ.
  • Motor-related γ.
  • Inter-regional synchronization in perception.
  • Perception-related γ.

    In lower frequency bands, oscillation abnormalities include the following:

    If we can draw any conclusions at this point in time, it might be that high-frequency oscillations are generally reduced in power/phase-locking, while low-frequency oscillations may be increased, and that inter-regional synchronization is impaired.

    Mechanisms underlying γ oscillation abnormalities
    The mechanisms underlying γ oscillations are perhaps the best understood out of all the oscillations, and the convergence between this research and postmortem studies of neural circuitry abnormalities in schizophrenia has spurred much of the interest in γ oscillations as potential biomarkers. Below is a summary of some of the most salient findings in this area:

    Inhibitory interneurons.

    • Fast-spiking, perisomatic-targeting, parvalbumin (PV)-expressing interneurons (chandelier and basket cells).
    Reduced synaptic connectivity.
    • Neuronal density appears to be increased in schizophrenia, but cortical volume is decreased. Thus, the interneuronal space containing dendrites and axons (neuropil) is reduced. May reflect reduced synaptic connectivity (Selemon and Goldman-Rakic, 1999).
    • Supported by decreases in:
      • Spine density, somal size, and dendritic fields of pyramidal cells.
      • Presynaptic markers.
    • Consistent with MRI evidence of cortical thinning, volume reduction.
NMDA receptor hypofunction.

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Boutros NN, Arfken C, Galderisi S, Warrick J, Pratt G, Iacono W (2008). The status of spectral EEG abnormality as a diagnostic test for schizophrenia. Schizophr Res 99:225–237. Abstract

Brenner CA, Sporns O, Lysaker PH, O’Donnell BF (2003). EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder. Am J Psychiatry 160:2238-2240. Abstract

Cho RY, Konecky RO, Carter CS (2006). Impairments in frontal cortical {γ} synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci USA 103:19878-19883. Abstract

Clementz BA, Keil A, Kissler J (2004). Aberrant brain dynamics in schizophrenia: delayed buildup and prolonged decay of the visual steady-state response. Cogn Brain Res 18:121-129. Abstract

Ferrarelli F, Huber R, Peterson MJ, Massimini M, Murphy M, Riedner BA, Watson A, Bria P, Tononi G (2007). Reduced sleep spindle activity in schizophrenia patients. Am J Psychiatry 2007 164:483-492. Abstract

Ford JM, Roach BJ, Faustman WO, Mathalon DH (2008). Out-of-synch and out-of-sorts: dysfunction of motor-sensory communication in schizophrenia. Biol Psychiatry 63:736-743. Abstract

Gallinat J, Winterer G, Herrmann CS, Senkowski D (2004). Reduced oscillatory γ-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing. Clin Neurophysiol 115:1863-1874. Abstract

Gonzalez-Burgos G, Lewis DA (2008). GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34:944-961. Abstract

Hajszan T, Leranth C, Roth RH (2006). Subchronic phencyclidine treatment decreases the number of dendritic spine synapses in the rat prefrontal cortex. Biol Psychiatry 60:639-644. Abstract

Homayoun H, Moghaddam B (2007). NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496-11500. Abstract

Hong LE, Summerfelt A, McMahon R, Adami H, Francis G, Elliott A, Buchanan RW, Thaker GK (2004). Evoked γ band synchronization and the liability for schizophrenia. Schizophr Res 70:293-302. Abstract

Javitt DC, Zukin SR (1991). Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301-1308. Abstract

Jin Y, Potkin SG, Sandman CA, Bunney Jr WE (1997). Electroencephalographic photic driving in patients with schizophrenia and depression. Biol Psychiatry 41:496-499. Abstract

Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM (2006). A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 26:1604-1615. Abstract

Krishnan GP, Vohs JL, Hetrick WP, Carroll CA, Shekhar A, Bockbrader MA, O’Donnell BF (2005). Steady state visual evoked potential abnormalities in schizophrenia. Clin Neurophysiol 116:614–624. Abstract

Krystal JH, D’Souza C, Mathalon D, Perry E, Belger A, Hoffman R (2003). NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacol 169:215–233. Abstract

Kwon JS, O’Donnell BF, Wallenstein GV, Greene RW, Hirayasu Y, Nestor PG, Hasselmo ME, Potts GF, Shenton ME, McCarley RW (1999). γ frequency-range abnormalities to auditory stimulation in schizophrenia. Arch Gen Psychiatry 56:1001-1005. Abstract

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O’Donnell BF, Hetrick WP, Bodkins M, Vohs JL, Bismark A, Skosnik PD, Johannesen JK, Carroll CA, Shekhar A (2006). Event-related potential abnormalities in bipolar disorder: relationship to symptoms, medication, and substance disorders. In New Developments in Mania Research (pp. 115-133). Hauppauge, NY: Nova Science Press.

Pinault D (2008). N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant {γ} oscillations in the rat neocortex. Biol Psychiatry 63:730-735. Abstract

Roach BJ, Mathalon DH (2008). Event-related EEG time-frequency analysis: an overview of measures and an analysis of early γ band phase locking in schizophrenia. Schizophr Bull 34:907–926. Abstract

Roopun AK, Cunningham MO, Racca C, Alter K, Traub RD, Miles A. Whittington MA (2008). Region-specific changes in γ and β2 rhythms in NMDA receptor dysfunction models of schizophrenia. Schizophr Bull 34:962-973. Abstract

Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry. 1999 Jan 1;45(1):17-25. Review. Abstract

Singer W (1999). Neuronal synchrony: a versatile code for the definition of relations? Neuron 24:49-65, 111-125. Abstract

Sirota A, Montgomery S, Fujisawa S, Isomura Y, Zugaro M, Buzsáki G (2008). Entrainment of neocortical neurons and γ oscillations by the hippocampal θ rhythm. Neuron 60:683–697. Abstract

Spencer KM, Nestor PG, Perlmutter R, Niznikiewicz MA, Klump MC, Frumin M, Shenton ME, McCarley RW (2004). Neural synchrony indexes disordered perception and cognition in schizophrenia. Proc Natl Acad Sci USA 101:17288-17293. Abstract

Spencer KM, Niznikiewicz MA, Shenton ME, McCarley RW (2008a). Sensory-evoked γ oscillations in chronic schizophrenia. Biol Psychiatry 63:744-747. Abstract

Spencer KM, Salisbury DF, Shenton ME, McCarley RW (2008b). γ-band auditory steady-state responses are impaired in first episode psychosis. Biol Psychiatry 64:369-375. Abstract

Teale P, Collins D, Maharajh K, Rojas DC, Kronberg E, Reite M (2008). Cortical source estimates of γ band amplitude and phase are different in schizophrenia. NeuroImage 42:1481-1489. Abstract

Uhlhaas PJ, Linden DEJ, Singer W, Haenschel C, Lindner M, Maurer K, Rodriguez E (2006). Dysfunctional long-range coordination of neural activity during Gestalt perception in schizophrenia. J Neurosci 26:8168-8175. Abstract

Wilson TW, Hernandez O, Asherin RM, Teale PD, Reite ML, Rojas DC (2008). Cortical γ generators suggest abnormal auditory circuitry in early-onset psychosis. Cereb Cortex 18:371–378. Abstract

Whittington MA, Traub RD (2003). Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26:676-682. Abstract

Winterer G, Weinberger DR (2004). Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 27:683-690. Abstract

Comments on Online Discussion
Comment by:  Didier Pinault
Submitted 12 December 2008 Posted 13 December 2008

Disruption of the signal-to-noise ratio in schizophrenia?
Brain rhythms are biomarkers of physiological and pathological, resting and active states. Peter Uhlhaas and Kevin Spencer have given extensive evidence relative to schizophrenia. They have further raised an important issue to discuss about the possible role of synchronized oscillations in the pathophysiology of such complex psychiatric disorder. To better understand the diverse alterations in rhythms observed in schizophrenic persons (Whittington, 2008), one strategy would be to apprehend the link between task-related synchronized oscillations and the associated state-related oscillations. The former oscillations are here considered as the signal whereas the latter as contributing to the basal activity or background noise.

From the findings obtained so far, it appears that the relation between gamma frequency (30-80 Hz) oscillations and schizophrenic symptoms is a conflicting field. For instance, increases and decreases in gamma frequency oscillations have...  Read more

View all comments by Didier Pinault

Comment by:  Georg Winterer (Disclosure)
Submitted 10 January 2011 Posted 10 January 2011

When my former group and I in Berlin, Germany, started in the middle of the 1990s to look into synchronization in schizophrenia, we explicitly decided not to analyze EEG γ (back then computational resources were still limited and you had to make decisions about what you really wanted to analyze). At that time, the work of Freeman and Malsburg in the 1980s and of Singer in the 1990s on γ oscillations (binding) was well known to us. Even so, we made this decision simply because we felt that this high-frequency component is too prone to (muscle) artifacts. (Anyone who has analyzed several thousands of clinical EEGs of schizophrenia patients knows what I am talking about.) In addition, there were a number of other animal and human studies around that clearly suggested that low-frequency synchrony could also be involved in binding (see Winterer and McCarley, 2011).

Although we were first in demonstrating abnormal low-frequency synchrony (termed signal-to-noise ratio) in schizophrenia (. Winterer et al., 2000;   Read more

View all comments by Georg Winterer
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