Thalamic dysfunction in schizophrenia: neurochemical, neuropathological, and in vivo imaging abnormalities
Introduction
Patients suffering from schizophrenia experience a wide range of symptoms, including paranoid delusions, hallucinations, blunted affect, social withdrawal, as well as cognitive and attentional deficits. These individuals are often unable to properly process stimuli, whether they are experiencing auditory or visual hallucinations, or are unable to identify social cues or focus their attention on a particular task (Andreasen et al., 1998). Many of these symptoms may stem from a primary deficit in sensory processing Oke and Adams, 1987, Jones, 1997, Scheibel, 1997, Andreasen et al., 1998. While prefrontal and temporal cortical dysfunction are typically thought to underlie the cognitive abnormalities seen in schizophrenia, more recent attention has focused on the thalamus, the brain's ‘central sensory switchboard’ (Steriade et al., 1997, p. 27). The thalamus plays a critical role in processing and integrating sensory information relevant to emotional and cognitive functions, and several lines of investigation now implicate thalamic dysfunction in the pathophysiology of schizophrenia Oke and Adams, 1987, Jones, 1997, Scheibel, 1997, Andreasen et al., 1998.
The thalamus is involved in information processing at multiple levels. It is composed of numerous topographically organized nuclei that process modality-specific input, such as somatosensory or visual information. Incoming sensory information is initially channeled to one of these nuclei before it is sent to the appropriate cortical region that processes the information, and in turn projects back to the thalamus (Jones, 1998). The thalamus is also critical for the regulation of states of consciousness, which can influence the ability of the cortex to receive and process information (Jones, 1997). Thalamic circuitry involves three main cell types: relay cells and inhibitory interneurons located in the dorsal thalamus, and neurons of the reticular nucleus (Jones, 1998; Fig. 1). Relay neurons project to the cortex and receive reciprocal input from these same cortical regions in addition to sensory afferent input. Local inhibitory neurons act on the dendrites of relay neurons and sensory afferent terminals in a given nucleus (Salt and Eaton, 1996). Reticular neuron cell bodies reside in the reticular nucleus, a thin sheet of γ-aminobutyric acid (GABA)ergic neurons that encompasses the dorsal thalamus. These neurons receive excitatory input from collateral fibers of the thalamocortical and corticothalamic projections coming into and going out of the dorsal thalamus (Fig. 1). The reticular neurons, in turn, send axons into the dorsal thalamus to gate relay neuron activity Salt and Eaton, 1996, Jones, 1998. Reticular neurons dictate the activity of dorsal thalamic relay cells, and, consequently, are able to influence the ability of the dorsal thalamus to relay incoming sensory information to the cortex (Jones, 1997).
Thalamic circuitry predominantly uses two neurotransmitters: glutamate and GABA (Fig. 1). Thalamocortical projections, as well as corticothalamic and sensory afferents to the dorsal thalamus all use glutamate as a primary neurotransmitter, which exerts its effect through both ionotropic (NMDA, AMPA, kainate) and metabotropic glutamate receptors (mGluRs) expressed throughout the thalamus. The reticular nucleus and intrinsic interneurons modulate thalamic tone via GABA, and certain thalamic nuclei (anterior ventral lateral and ventral medial) receive GABAergic input from the internal segment of the globus pallidus, ventral pallidum, and substantia nigra pars reticulata (Steriade et al., 1997 pg 129). The thalamus also receives substantial noradrenergic, serotonergic, and cholinergic innervation, all of which likely modulate glutamatergic and GABAergic inputs (Jones, 1998). The thalamus has generally been thought to lack dopaminergic input Moore and Bloom, 1978, Steriade et al., 1997. Several studies, however, have demonstrated the presence of dopamine (DA) Brown et al., 1979, Goldman-Rakic and Brown, 1981, Oke et al., 1983, Oke et al., 1988, DA-positive axons (using antibodies against tyrosine hydroxylase and the DA membrane transporter) (Melchitzky and Lewis, 2001), and DA receptors Kessler et al., 1993, Hall et al., 1996, Suzuki et al., 1998, Gurevich and Joyce, 1999 in the mediodorsal (MD) nucleus and other thalamic nuclei. Furthermore, electrophysiological studies have shown that DA modulates the excitability of cells in the MD thalamus of rat Lavin and Grace, 1998a, Lavin and Grace, 1998b, suggesting that thalamic DA input may be functionally important for MD thalamus-prefrontal cortical circuitry.
Numerous postmortem and in vivo imaging studies have found structural and metabolic abnormalities in the thalamus in schizophrenia, but few studies have examined the neurochemical substrates that may accompany these changes. Much of this work, to date, has focused on glutamatergic abnormalities in the thalamus, in part because it is a predominant neurotransmitter used in the thalamus, and because glutamatergic dysfunction has been hypothesized to be involved in schizophrenia (Goff and Coyle, 2001). Additionally, several studies have examined markers of both GABA and DA neurotransmission in the thalamus in schizophrenia. We review these neurochemical findings, as well as the growing body of postmortem and in vivo imaging evidence that supports the hypothesis of thalamic dysfunction in schizophrenia.
Section snippets
Glutamate
Glutamate has been implicated in the pathophysiology of schizophrenia, in part, because non-competitive NMDA receptor (NMDAR) antagonists like phencyclidine produce a schizophreniform psychosis and cognitive deficits in non-psychiatrically ill subjects, and exacerbate these symptoms in patients with schizophrenia (Lahti et al., 1995). Clinical trials have shown that enhancing NMDAR function with agonists of the glycine/d-serine co-agonist site of the NMDAR, or ampakines, which promote AMPA
MRI evidence of reduced thalamic volume in schizophrenia
Using MRI, several groups have reported reduced thalamic volume in schizophrenia Andreasen et al., 1990, Andreasen et al., 1994, Flaum et al., 1995, Buchsbaum and Hazlett, 1998, Gur et al., 1998, Staal et al., 1998, Dasari et al., 1999, Ettinger et al., 2001, Gilbert et al., 2001, Konick and Friedman, 2001, although others have found no change Jernigan et al., 1991, Corey-Bloom et al., 1995, Portas et al., 1998, Arciniegas et al., 1999, Hazlett et al., 1999, Byne et al., 2001, Bagary et al.,
PET And SPECT findings
While MRI and postmortem studies have identified structural abnormalities in several brain regions in schizophrenia, studies using functional brain imaging techniques like PET and SPECT have observed metabolic abnormalities in a many of these same structures. Many early PET studies found reduced cerebral blood flow in frontal cortical regions in patients with schizophrenia, which may be associated with the cognitive and attentional deficits commonly present in this illness (for reviews see
Conclusions
Abundant postmortem and in vivo imaging evidence, and more recent neurochemical data, implicate thalamic dysfunction in schizophrenia. Cognitive and sensory deficits that persist in schizophrenia may be associated with a disturbance of cortico-thalamic circuitry. Indeed, numerous PET studies have reported reduced thalamic and prefrontal cortical metabolism in patients with schizophrenia, particularly when they are engaged in complex cognitive tasks. Thalamic hypoactivity may be associated with
References (151)
- et al.
Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients
Lancet
(1997) - et al.
The thalamus and the schizophrenia phenotype: failure to replicate reduced volume
Biol. Psychiatry
(1999) - et al.
Reduced NAA in the thalamus and altered membrane and glial metabolism in schizophrenic patients detected by 1H-MRS and tissue segmentation
Schizophr. Res.
(2001) - et al.
Importance of pharmacologic control in PET studies: effects of thiothixene and haloperidol on cerebral glucose utilization in chronic schizophrenia
Psychiatry Res.
(1991) - et al.
Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects
Neuroscience
(1996) - et al.
Uncoupling of GABA(A) and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain
Brain Res.
(1997) - et al.
A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives
Biol. Psychiatry
(1998) - et al.
Regional distribution of monoamines in the cerebral cortex and subcortical structures of the rhesus monkey: concentrations and in vivo synthesis rates
Brain Res.
(1979) - et al.
Functional brain imaging and aging in schizophrenia
Schizophr. Res.
(1997) - et al.
Positron emission tomography studies of basal ganglia and somatosensory cortex neuroleptic drug effects: differences between normal controls and schizophrenic patients
Biol. Psychiatry
(1987)
Gamma-aminobutyric acid in the brain in schizophrenia
Lancet
A postmortem study of the mediodorsal nucleus of the thalamus in schizophrenia
Schizophr. Res.
A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis
Brain Res. Bull.
Schizophrenia and anteroventral thalamic nucleus: selective decrease of parvalbumin-immunoreactive thalamocortical projection neurons
Psychiatry Res.
The ventral lateral posterior nucleus of the thalamus in schizophrenia: a post-mortem study
Psychiatry Res.
Volumes of association thalamic nuclei in schizophrenia: a postmortem study
Schizophr. Res.
A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls
Psychiatry Res.
Magnetic resonance imaging of the thalamus in male patients with schizophrenia
Schizophr. Res.
Proton magnetic resonance spectroscopy (1H-MRS) of the thalamus in schizophrenia
Eur. Psychiatr.
Multidimensional analysis of the concentrations of 17 substances in the CSF of schizophrenics and controls
Biol. Psychiatry
Regional changes of monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys
Neuroscience
Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons
Neuropsychopharmacology
[3H]muscimol binding sites increased in autopsied brains of chronic schizophrenics
Life Sci.
Regional proton magnetic resonance spectroscopy in schizophrenia and exploration of drug effect
Psychiatry Res.
Clustering and enhanced activity of an inwardly rectifying potassium channel, Kir4.1, by an anchoring protein, PSD-95/SAP90
J. Biol. Chem.
The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia
Neuropsychopharmacology
In vivo neurochemistry of the brain in schizophrenia as revealed by magnetic resonance spectroscopy
Biol. Psychiatry
Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride
Brain Res.
Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia
Neurosci. Lett.
Meta-analysis of thalamic size in schizophrenia
Biol. Psychiatry
Cerebrospinal fluid amino acid concentrations in chronic schizophrenia
Psychiatry Res.
Increased dopamine transmission in schizophrenia: relationship to illness phases
Biol. Psychiatry
Catching up on schizophrenia: natural history and neurobiology
Neuron
Amino acid patterns in schizophrenia: some new findings
Psychiatry Res.
Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics
Arch. Gen. Psychiatry
Monoamine metabolites and amino acids in serum from schizophrenic patients before and during sulpiride treatment
Psychopharmacology
Magnetic resonance imaging of the brain in schizophrenia. The pathophysiologic significance of structural abnormalities
Arch. Gen. Psychiatry
Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London
Arch. Gen. Psychiatry
Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging
Science
Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal–thalamic–cerebellar circuitry
Proc. Natl. Acad. Sci. U. S. A.
“Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical–subcortical–cerebellar circuitry?
Schizophr. Bull.
A magnetization transfer analysis of the thalamus in schizophrenia
J. Neuropsychiatry Clin. Neurosci.
The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic transmission
J. Neurosci.
Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter
Science
Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics
J. Neurosci.
Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain
Synapse
Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging
Am. J. Psychiatry
Plasma amino acids in relation to cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy controls
Br. J. Psychiatry
Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method
Proc. Natl. Acad. Sci. U. S. A.
Localization of postsynaptic density-93 to dendritic microtubules and interaction with microtubule-associated protein 1A
J. Neurosci.
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