Schizophrenia patients exhibit impairments across multiple clinical, cognitive, and functional domains. A fundamental abnormality of the timing and/or efficiency of neural processes across disparate brain regions (i.e., cortico-cortical communications) may underlie many of the deficits in schizophrenia. Because gamma synchrony is temporally correlated with many cognitive processes, probing patterns of gamma activation may shed light on the functional integrity of neural circuits in schizophrenia and related disorders.

Hallucinations do not originate in a single region of the brain, the thalamus, and cannot be traced back to a single pathological mechanism. They emerge from the complex interaction of several brain regions, and are not necessarily the result of sensory impairment or the effect of a defective filter. In the case of schizophrenia, hallucinations are accessory symptoms, in Bleuler's sense, and are thus not central to this disorder.

Behrendt & Young (B&Y) propose that a dysfunction in the reticular thalamic nucleus contributes to disinhibition of specific thalamic nuclei, allowing cortical attention mechanisms to engage thalamic relay neurons, causing underconstrained activation of the cortex and hallucinations. The following hypothesis challenges the notion of impaired sensory gating by providing the alternative view that hypofrontality reduces the power of incoming stimuli, causing internal drives to override consciousness, resulting in hallucinations.

The idea that experience is essentially subjective rather than of the real world is paradoxical and deeply flawed. The external world is, much more than a mere constraint, essential to meaningfully describe experience and neural activity. This is illustrated by an analysis of the phenomenology of veridical perception and by the study of experience in psychopathology by the Experience Sampling Method (ESM).

We can live in fantasy only if we survive in reality. Visual experience that carries information about the real world – that is, normal perception – serves that goal. Normal perception is not merely constrained hallucination, and it can usually be distinguished from internally generated images, with which it is rarely confused. Modulatory processes, such as attention, do indeed affect most levels of perceptual processing, but they do so without invalidating the transmission of the signals that they modulate.

Behrendt & Young's (B&Y's) theory offers a potentially important perspective on the neurobiology of schizophrenia, but it remains incomplete. In addition to bottom-up contributions, such as those associated with disturbances in sensory constraints on cognitive processes, a comprehensive model requires the integration of the consequences of abnormal top-down modulation of input processing for the evolution of “underconstrained” perceptions. Dysfunctional cholinergic modulation of input functions represents a necessary mechanism for the generation of false perceptions.

Behrendt & Young (B&Y) propose an explanation for schizophrenia in terms of a cortical default in the interaction between consciousness and cognition. However, schizophrenia more likely involves miscommunication between subcortical and cortical affective circuits in the brain, a default in the interaction between consciousness and emotion. The typical “affective” nature of hallucinations in schizophrenia provides compelling evidence for subcortical involvement.

This commentary challenges the argument that the diathesis for hallucinations is equivalent to that for schizophrenia. Evidence against this comes from data on the prevalence of hallucinations in schizophrenia, their nonspecificity, and their relationships with moderating variables. We also highlight, however, the manner in which the Behrendt & Young (B&Y) hypothesis extends recent neuroscientific theories of schizophrenia, and its potential treatment applications.

I propose that hyperactivity (or increased numbers) of neurons in the brainstem reticular core promote hallucinations by excessive excitation, coupled with disinhibition, of target thalamocortical neurons. This idea stems from animal experiments using kainate-induced overexcitation of midbrain reticular neurons leading to hallucinatory-type behavior during wakefulness, as well as from data in schizophrenic patients showing an increased number of neurons in mesopontine cholinergic neurons.

Gamma rhythms are associated with external and internal sensory processing. Within the conceptual framework of “top-down” and “bottom-up” processing, this suggests that gamma represents a format common to both camps. As these oscillations facilitate communication in the temporal domain, they may represent a mechanism by which top-down and bottom-up processing can interact. A breakdown in this interaction may lead to hallucinations.

The commentators provide a wealth of additional neurobiological data that ought to be integrated in a comprehensive model. This response article, however, focuses on clarification of conceptual queries, thereby outlining the proposed theory of hallucinations more sharply, discussing its relationship with schizophrenia, and explaining why underconstrained thalamocortical activation may well be a candidate mechanism responsible for acute schizophrenic symptoms other than hallucinations.

Schizophrenia is a worldwide, prevalent disorder with a multifactorial but highly genetic aetiology. A constant prevalence rate in the face of reduced fecundity has caused some to argue that an evolutionary advantage exists in unaffected relatives. Here, I critique this adaptationist approach, and review – and find wanting – Crow's “speciation” hypothesis. In keeping with available biological and psychological evidence, I propose an alternative theory of the origins of this disorder. Schizophrenia is a disorder of the social brain, and it exists as a costly trade-off in the evolution of complex social cognition. Paleoanthropological and comparative primate research suggests that hominids evolved complex cortical interconnectivity (in particular, frontotemporal and frontoparietal circuits) to regulate social cognition and the intellectual demands of group living. I suggest that the ontogenetic mechanism underlying this cerebral adaptation was sequential hypermorphosis and that it rendered the hominid brain vulnerable to genetic and environmental insults. I argue that changes in genes regulating the timing of neurodevelopment occurred prior to the migration of Homo sapiens out of Africa 100,000–150,000 years ago, giving rise to the schizotypal spectrum. While some individuals within this spectrum may have exhibited unusual creativity and iconoclasm, this phenotype was not necessarily adaptive in reproductive terms. However, because the disorder shared a common genetic basis with the evolving circuitry of the social brain, it persisted. Thus schizophrenia emerged as a costly trade-off in the evolution of complex social cognition.

Burns proposes an intriguing hypothesis by suggesting that the “schizophrenia genes” might not be regulatory genes themselves, but rather closely associated with regulatory genes directly involved in the proper growth of the social brain. We point out that this account would benefit from incorporating the effects of localized lesions and aberrant hemispheric asymmetry on cortical connectivity underlying the social brain. In addition, we argue that the evolutionary framework is superfluous.

Dysfunctions of the neural circuits that implement social behavior are necessary but not a sufficient condition to develop schizophrenia. We propose that schizophrenia represents a disease of general connectivity that impairs not only the “social brain” networks, but also different neural circuits related with higher cognitive and perceptual functions. We discuss possible mechanisms and evolutionary considerations.

An evolutionary theory of schizophrenia needs to address all symptoms associated with the condition. Burns' framework could be extended in a way embracing behavioural signs such as catatonia. Burns' theory is, however, not specific to schizophrenia. Since no one single symptom exists that is pathognomonic for “schizophrenia,” an evolutionary proposal of psychiatric disorders raises the question whether our anachronistic psychiatric nosology warrants revision.

I agree with Burns that an evolutionary theory is required, but I question his multifactorial premise. The arguments for an evolutionary theory are stronger, and one that is more precise than that presented by Burns has already been formulated. This theory, that schizophrenia is “the price that Homo sapiens pays for language,” (Crow 1997a; 2000b, 2004c), generates testable predictions absent from Burns' presentation.

There is evidence that people with schizophrenia have difficulties in some (recently evolved) competencies for processing social information. However, a case can be made that vulnerabilities can also lie in (previously evolved) threat and safeness processing systems. Evolutionary models may need to consider interactions between genetic sensitivities, early experiences of threat/safeness, and later cognitive vulnerabilities. Psychological treatments must address issues of experienced threat and safeness before working on more cognitive competencies.

While schizophrenia may be genetically determined up to a point, neither it nor its nearest relatives offer any sort of reproductive advantage to its sufferers. Instead, from an evolutionary point of view, schizophrenia is benign – it neither promotes nor inhibits survival to reproduction. Because it is benign, its rate of occurrence should remain fairly constant over time.

Multidisciplinary studies indicate that auditory hallucinations may arise from speech perception neurocircuitry without disrupted theory of mind capacities. Computer simulations of excessive pruning in speech perception neural networks provide a model for these hallucinations and demonstrate that connectivity reductions just below a “psychotogenic threshold” enhance information processing. These data suggest a process whereby vulnerability to schizophrenia is maintained in the human population despite reproductive disadvantages of this illness.

If alleles that predispose to schizophrenia have reduced Darwinian fitness, their persistence in modern times is puzzling. Burns identifies the evolutionary genetics of schizophrenia as a central issue, but his treatment of it is not clear. Recent advances in evolutionary genetics can help explain the persistence of alleles that predispose to debilitating disorders such as schizophrenia, and can buttress Burns' core argument.