Neural Synchrony indexes disordered perception and cognition in schizophrenia

Department of Psychiatry, Veterans Affairs Boston Healthcare System, Harvard Medical School, Psychiatry 116A, 940 Belmont Street, Brockton, MA 02301, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2005; 101(49):17288-93. DOI: 10.1073/pnas.0406074101
Source: PubMed


Current views of schizophrenia suggest that it results from abnormalities in neural circuitry, but empirical evidence in the millisecond range of neural activity has been difficult to obtain. In pursuit of relevant evidence, we previously demonstrated that schizophrenia is associated with abnormal patterns of stimulus-evoked phaselocking of the electroencephalogram in the gamma band (30-100 Hz). These patterns may reflect impairments in neural assemblies, which have been proposed to use gamma-band oscillations as a mechanism for synchronization. Here, we report the unique finding that, in both healthy controls and schizophrenia patients, visual Gestalt stimuli elicit a gamma-band oscillation that is phase-locked to reaction time and hence may reflect processes leading to conscious perception of the stimuli. However, the frequency of this oscillation is lower in schizophrenics than in healthy individuals. This finding suggests that, although synchronization must occur for perception of the Gestalt, it occurs at a lower frequency because of a reduced capability of neural networks to support high-frequency synchronization in the brain of schizophrenics. Furthermore, the degree of phase locking of this oscillation is correlated with visual hallucinations, thought disorder, and disorganization in the schizophrenia patients. These data provide support for linking dysfunctional neural circuitry and the core symptoms of schizophrenia.

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    • "Specifically, NMDA-R hypofunction on parvalbumin positive inhibitory interneurons results in decreased inhibitory g-aminobutyric acid (GABA) input to (and therefore disinhibition of) pyramidal cells and hence a loss of balance between excitation and inhibition in prefrontal cortex [Lewis et al., 2012; Murray et al., 2014; Pinotsis et al., 2014]. These abnormalities may be linked to neurophysiological disorganisation [D ıez et al., 2014], cognitive dysfunction and the development of symptoms of psychosis [Ahn et al., 2011; Lewis et al., 2008; Spencer et al., 2004]. "
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    ABSTRACT: The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task-for 24 patients with psychosis, 25 of their first-degree unaffected relatives, and 35 controls-and DCM was used to estimate the excitability (modeled as self-inhibition) of (source-specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context-dependent (condition-specific) and context-independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis. Hum Brain Mapp, 2015. © 2015 The Authors Human BrainMapping Published byWiley Periodicals, Inc.
    Human Brain Mapping 10/2015; DOI:10.1002/hbm.23035 · 5.97 Impact Factor
    • "Recent studies have supported an important role for inhibitory neurons, such as cortical interneurons (GABAergic neurons), in the development of the cortex. In addition, impairment in this cell population has been linked to neuropsychiatric disorders such as autism and schizophrenia (Acosta and Pearl, 2003; Lewis and Levitt, 2002; Rubenstein and Merzenich, 2003; Spencer et al., 2004). Although GABAergic interneurons make up a relatively small fraction of the total number of cells in the neocortex, even small changes in the balance of excitation and inhibition could have profound effects on key neurological functions, including cognition, sensory perception, language and spatial reasoning (Lui et al., 2011). "
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    ABSTRACT: GABAergic synaptic transmission is known to play a critical role in the assembly of neuronal circuits during development and is responsible for maintaining the balance between excitatory and inhibitory signaling in the brain during maturation into adulthood. Importantly, defects in GABAergic neuronal function and signaling have been linked to a number of neurological diseases, including autism spectrum disorders, schizophrenia, and epilepsy. With patient-specific induced pluripotent stem cell (iPSC)-based models of neurological disease, it is now possible to investigate the disease mechanisms that underlie deficits in GABAergic function in affected human neurons. To that end, tools that enable the labeling and purification of viable GABAergic neurons from human pluripotent stem cells would be of great value.
    Molecular and Cellular Neuroscience 08/2015; 68. DOI:10.1016/j.mcn.2015.08.007 · 3.84 Impact Factor
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    • "| to optimize learning . Conversely , our interface - controlled non - theta state may be a drug - free , non - lesion model of psychiatric / cognitive disorders such as schizophrenia , autism and age - related memory impairments , thought to result from desynchronization of critical brain systems ( Behrendt and Young , 2004 ; Spencer et al . , 2004 ; Asaka et al . , 2005 ; Donkers et al . , 2011 ; Doesburg et al . , 2013 ) . Continuation of this approach will enhance our knowledge of the roles of LFPs as well as their relation to signals in other bandwidths and time frames ( Bullock , 1997 ) , with the goal of a comprehensive description of electrophysiological mechanisms of infor"
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    ABSTRACT: Neurobiological oscillations are regarded as essential to normal information processing, including coordination and timing of cells and assemblies within structures as well as in long feedback loops of distributed neural systems. The hippocampal theta rhythm is a 3-12 Hz oscillatory potential observed during cognitive processes ranging from spatial navigation to associative learning. The lower range, 3-7 Hz, can occur during immobility and depends upon the integrity of cholinergic forebrain systems. Several studies have shown that the amount of pre-training theta in the rabbit strongly predicts the acquisition rate of classical eyeblink conditioning and that impairment of this system substantially slows the rate of learning. Our lab has used a brain-computer interface that delivers eyeblink conditioning trials contingent upon the explicit presence or absence of hippocampal theta. A behavioral benefit of theta-contingent training has been demonstrated in both delay and trace forms of the paradigm with a two- to four-fold increase in learning speed. This behavioral effect is accompanied by enhanced amplitude and synchrony of hippocampal local field potentials, multiple-unit excitation, and single-unit response patterns that depend on theta state. Additionally, training in the presence of hippocampal theta has led to increases in the salience of tone-induced unit firing patterns in the medial prefrontal cortex, followed by persistent multi-unit activity during the trace interval. In cerebellum, rhythmicity and precise synchrony of stimulus time-locked local field potentials with those of hippocampus occur preferentially under the theta condition. Here we review these findings, integrate them into current models of hippocampal-dependent learning and suggest how improvement in our understanding of neurobiological oscillations is critical for theories of medial temporal lobe processes underlying intact and pathological learning.
    Frontiers in Systems Neuroscience 04/2015; DOI:10.3389/fnsys.2015.00050
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