Disrupted Cortical Conductivity in Schizophrenia: TMS–EEG Study

Cerebral Cortex January 2014;24:211–221 doi:10.1093/cercor/bhs304 Advance Access publication October 5, 2012 Disrupted Cortical Conductivity in Schizophrenia: TMS–EEG Study Marina Frantseva1, Jie Cui2, Faranak Farzan1, Lakshminarayan V. Chinta1, Jose Luis Perez Velazquez3 and Zafiris Jeffrey Daskalakis1 1 Schizophrenia Program, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada, 2Visual Neuroscience Lab, Division of Neurobiology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA, 3Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada Address correspondence to Marina Frantseva, Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, Canada. Email: Keywords: connectivity, electroencephalography, neuronal synchrony, schizophrenia, transcranial magnetic stimulation Introduction Schizophrenia is a heterogeneous disorder characterized by a complex constellation of seemingly unrelated symptoms, including hallucinations, delusions, thought disorder, affective flattening, and pronounced cognitive deficits. Recent evidence supports the notion that a wide range of deficits in schizophrenia may result from a failure to integrate the activity of local and distributed neural circuits. This includes abnormal power and synchronization patterns of induced or evoked electroencephalography (EEG) rhythmic activity in both medicated and medication-naive patients (Spencer et al. 2004; Cho et al. 2006; Uhlhaas et al. 2006; Minzenberg et al. 2010) as well as decreased entrainment of oscillatory activity, primarily in high-frequency bands, in response to a steady-state stimulation (Kwon et al. 1999). Impaired ability of distributed neuronal networks to integrate information in schizophrenia has been attributed to abnormalities in the rhythm-generating neuronal networks, such as inhibitory interneurons (Lewis et al. 2005). The crucial role of inhibitory deficits in the pathophysiology of schizophrenia © Crown Copyright 2012. has been suggested by abnormalities in the functional integrity, morphology, and distribution of inhibitory interneurons in schizophrenic patients (Lewis et al. 2008). Further support for impaired inhibitory neurocircuits in schizophrenia is provided by evidence of significant deficits in intracortical inhibition in response to transcranial magnetic stimulation (TMS) in patients with schizophrenia (Daskalakis et al. 2002). These deficits have also been documented in first-episode schizophrenia patients (Wobrock et al. 2008) and are more pronounced in unmedicated patients (Daskalakis et al. 2002). Despite ample evidence linking affective and cognitive symptoms of schizophrenia with abnormalities of neural oscillatory activity (Uhlhaas et al. 2006), to date, we have a little understanding of how impaired synchrony between distributed neuronal networks translates into specific symptoms of schizophrenia. Current theories of cognitive functioning associate perceptual awareness with long-range synchronous rhythmic oscillatory activity. Intricate loops of feedback and feed-forward inhibition are known to segregate the activated neuronal assemblies into fine spatial and temporal domains specific to the incoming stimulus, which thus generate geometrically discrete rhythmic oscillations in distributed neuronal networks (Llinas et al. 2005). Binding of the multisensory inputs into a coherent cognitive experience is reliant on this inhibitory rhythm-generating “clustering,” as diminution of γ-aminobutyric acid release (GABAergic) inhibition has been shown to not only distort synchronized brain activity (Fingelkurts et al. 2004), but also alter perceptual selectivity (Wang et al. 2000, 2002). There is substantial theoretical and empirical evidence indicating that inhibition determines the spread of cortical activation by sculpting oscillatory patterns in time and space. Blocking inhibition has been shown to alter spatial and temporal patterns of neuronal activity, resulting in lateral spread of stimulation-induced neuronal activation in in vitro model systems (Contreras and Llinas 2001). Spatio-temporal patterns of spreading synaptic activity in response to stimulation were also reported in rat brain slices in the presence of both, dopamine and the GABAergic antagonist, bicuculline, 2 neurotransmitter mechanisms implicated in the pathophysiology of schizophrenia (Bandyopadhyay et al. 2005). It is possible, therefore, that deficient inhibitory neurocircuits lead to disrupted signal propagation of neuronal excitation in schizophrenia brains. Hence, we hypothesized that deficits in inhibitory neuronal networks, as has reliably demonstrated in patients with schizophrenia, may ultimately result in excessive spread of neuronal excitation in response to an incoming stimulus in the brains of patients with schizophrenia. However, addressing this question in live humans is not a trivial task. A recent Schizophrenia is conceptualized as a failure of cognitive integration, and altered oscillatory properties of neurocircuits are associated with its symptoms. We hypothesized that abnormal characteristics of neural networks may alter functional connectivity and distort propagation of activation in schizophrenic brains. Thus, electroencephalography (EEG) responses to transcranial magnetic stimulation (TMS) of motor cortex were compared between schizophrenia and healthy subjects. There was no difference in the initial response. However, TMS-induced waves of recurrent excitation spreading across the cortex were observed in schizophrenia, while in healthy subjects the activation faded away soon after stimulation. This widespread activation in schizophrenia was associated with increased oscillatory activities in the proximal central leads and in fronto-temporo-parietal leads bilaterally. A positive correlation was found between increased TMS-induced cortical activation in gamma frequency and positive symptoms of schizophrenia, while negative symptoms were correlated with activation in theta and delta bands. We suggest that excessive activation in response to stimulation in schizophrenia brains may lead to abnormal propagation of the signal that could potentially result in aberrant activity in areas remote from the activation origin. This mechanism may account for the positive symptoms of schizophrenia and could worsen signal to noise deficits, jeopardizing adequate information processing with ensuing cognitive deficits. Materials and Methods Participants We studied 16 patients (mean age 36.7 ± 10.4 years; 12 males, 4 females) with a diagnostic and statistical manual of mental disorders (DSM) diagnosis of schizophrenia or schizoaffective disorder confirmed by the structured clinical interview for DSM IV and 16 healthy subjects (mean age 36.1 ± 7.9; 11 males, 5 females). Fourteen of 16 patients with schizophrenia were treated with antipsychotic medications (clozapine, n = 6, (...truncated)