Evidence for a role of TRN deficits in schizophrenia is fairly recent, but it comes from both animal and human studies. Electrophysiological and pharmacological studies in rodents have shown that dysfunctions of the TRN result in deficits of auditory gating and attentional shift,2,54
2 core features of schizophrenia known to be defective in medication-naive, first-break, as well as chronic schizophrenic patients.55–57
Furthermore, pharmacological studies in the rat TRN have demonstrated metabolic and histopathological changes caused by N-Methyl-D-aspartic acid (NMDA) receptor antagonists, including phencyclidine (PCP) and ketamine, which can produce psychotic symptoms in healthy individuals.58–62
A genetic study in the developing mouse brain has revealed that TRN neurons express high levels of a gene associated with schizophrenia, DISC-1 (disrupted in schizophrenia).63
Finally, 2 recent hd-EEG sleep studies in humans have shown that patients with schizophrenia had marked deficits in sleep spindles, which are generated by the TRN, compared with healthy and psychiatric controls. These findings are summarized in , along with the information on the type of study and the species on which the study was conducted. These findings are presented more in detail below.
TRN Findings Related to The Neurobiology of Schizophrenia
Auditory gating refers to a reduced responsiveness (habituation) to repetitive stimulation and is measured as the ratio of the responses to 2 consecutive stimuli (S2/S1). An increased S2/S1, which indicates reduced auditory gating, has been consistently reported by electrophysiological studies in schizophrenics,64–66
and in a recent functional Magnetic Resonance Imaging (fMRI) study, in which schizophrenics showed an increased hemodynamic response in the thalamus during an auditory gating paradigm, it was suggested that the TRN may be responsible for such gating deficit.67
An involvement of the TRN in sensory gating is also supported by a recent study employing single-unit recordings in anesthetized rodents, which demonstrated gated responses in TRN neurons, as reflected by a reduced number of spikes to the second of 2 paired tones played a second apart.2
In this study, the authors also tested the effects of amphetamine, a dopamine agonist that can induce psychosis, and of haloperidol, a dopamine antagonist prescribed as an antipsychotic medication, on TRN auditory gating and found that amphetamine disrupted it, while haloperidol reversed such deficit.2
Attentional deficits are commonly present in schizophrenics.57
In a study aimed at reproducing these deficits in an animal model of schizophrenia, PCP was injected in rats to test for attentional shift impairments within and across stimulus dimensions (ie, spatial location and level of illumination). Attentional shift refers to the ability to move the focus of attention from one object to another, and it is a top-down mechanism regulated by the frontal cortex in combination with thalamic nuclei.68
PCP selectively impaired rats’ ability to shift attention across stimulus dimensions or extradimensional shifting. These attentional impairments were associated with reduced expression of Zif-268 and parvalbumin, 2 markers of local neuronal activity, in the infralimbic cortex and in the TRN.54
Other pharmacological studies investigating the effects of PCP on the rat brain found induced metabolic hypofunction within the prefrontal cortex, the auditory system, and the TRN, which were reversed after coadministration of typical (haloperidol) or atypical (clozapine) antipsychotics with PCP.58,59
PCP could also induce excitotoxic lesions in the posterior cingulate and retrosplenial cortices of rats following injections in the anterior thalamus. These lesions were likely due to reduced inhibitory control of the TRN on anterior thalamic nuclei, which in turn determined excessive activation (excitotoxicity) of corticolimbic areas. Of importance, these excitotoxic effects on the rat brain could be prevented by administering antipsychotic medications, such as haloperidol and clozapine.60–62
The DISC1 gene, located on chromosome 1q42, has been associated with schizophrenia by multiple human genetic studies.69
A recent study investigating the expression of DISC1 in the mouse brain found that it was expressed only in some brain structures, including hippocampus, part of the neocortex, hyphothalamus, stria terminalis, and TRN. Furthermore, in the mouse TRN, DISC1 was highly expressed during development, in a period when corticothalamic connections take shape. Other studies in rats have shown that the TRN and the perireticular nucleus, a narrow sheet of cells surrounding the TRN, are significantly larger relative to their adult size during development, when corticothalamic and thalamocortical pathways are first formed, thus suggesting that these thalamic nuclei may be critically implicated in this process.70
Based on these results, which, however, need to be replicated in species with a more complex corticothalamic circuitry, it was suggested that the TRN may play a critical role in the ontogenesis of connections within the thalamocortical system and that deficits in the TRN may be implicated in the neurodevelopmental vulnerability to schizophrenia.63
Consistent with these findings from animal studies, 2 sleep hd-EEG studies in humans have recently provided suggestive evidence for TRN defects in schizophrenia patients.71,72
An initial study found that 18 schizophrenics had marked deficits in TRN-generated NREM sleep spindles.9
Schizophrenics showed significant reductions in spindle duration, amplitude, number, and integrated spindle activity (ISA), calculated by integrating spindle amplitude over time, compared with 17 healthy controls and 15 depressed patients in the first NREM episode. A follow-up study extended these findings to 49 schizophrenics in whole-night recordings and established that nonschizophrenic patients taking antipsychotics had no spindle activity reduction, thus indicating that spindle deficits were not simply due to medications. Deficits in spindle number and ISA had an effect size (ES) ≥2.21, corresponding to ≥85% separation between schizophrenics and control subjects (), and similar ES were observed employing a 14-channel, low-density montage that included C1 and CPz, the channels with highest ES for the hd-EEG analysis. Additionally, in schizophrenics, both spindle number (at C1) and ISA (at CPz) were inversely correlated to the positive symptoms of the Positive and Negative Symptoms Scales. Given the magnitude of spindle deficits and their correlation with clinical symptoms in schizophrenics, these findings suggest that reduced TRN function may be implicated in the neurobiology of schizophrenia and may contribute to its clinical features.
Fig. 2. Spindles Deficits in Schizophrenics Have High Effect Size (ES); Can Be Detected With A Few Electroencephalographic (EEG) Channels; and Correlate With Clinical Symptoms. (A) The top trace shows 20 s of non-rapid eye movement (NREM) sleep, with vertical (more ...)
At this stage we can only speculate about the contribution of TRN deficits to the clinical symptoms of schizophrenia, which include hallucinations, delusions, as well as attentional, learning, and memory deficits. Auditory hallucinations are thought to reflect a reduced ability to distinguish externally generated stimuli, which are relayed by thalamocortical sensory pathways, from internally generated inputs, which are processed by corticothalamic circuits.73
Intriguingly, a study using juxtacellular recordings and labeling techniques has recently shown that the rat auditory TRN receives tonotopically organized afferents from both the cortex and the thalamus.74
A defect in the TRN may therefore account for the simultaneous impairment of thalamocortical and corticothalamic auditory circuits in schizophrenia. Furthermore, a reduced inhibitory control of the TRN on other thalamic nuclei would increase the response of thalamocortical neurons to internally cortically generated inputs, which in turn would facilitate hallucinatory experiences. A reduced activity of TRN neurons, as indicated by decreased cholinergic binding, has been reported in a postmortem study in schizophrenics and patients with Lewy bodies dementia, a disorder characterized by visual hallucinations.75
Together with hallucinations, patients with schizophrenia commonly experience delusions. Delusional thoughts tend to arise in a state of hypervigilance, characterized by an increased neuronal activity and an enhanced response to incoming inputs. It is therefore possible that a reduced inhibitory control of the TRN on thalamocortical activity may result in hyperactivation of the cortex, which, in turn, may produce psychotic delusional symptoms.
Schizophrenics also report cognitive deficits and especially attentional impairments.76
The TRN has long been viewed as critical for attention regulation, as indicated in the searchlight hypothesis.68
This hypothesis suggests explicitly that the TRN is involved in rapidly moving the center of attention between external inputs, based on a decision made by the frontal cortex. Recent electrophysiological studies in primates have provided experimental evidence for the involvement of the TRN in the control of attention and have shown how TRN dysfunctions may result in attentional deficits.77,78
Other cognitive processes found to be impaired in schizophrenia patients are learning and memory.76
While many factors, including changes in the level of attention, decreased motivation, and presence of active symptoms may affect these cognitive processes, it is intriguing that such processes are critically regulated during sleep by sleep-specific rhythms, including sleep spindles.79
Higher spindle activity is associated with better performances in verbal memory, visuospatial memory, as well as declarative learning tasks.79
A defective TRN function, which initiates spindle oscillations, may therefore interfere with the ability to learn as well as with memory consolidation processes and may account for some of the cognitive impairments found in schizophrenia.