Reply to “Role of Thalamus in Sleep–Wake Cycle Regulation”

Dr Guaraldi and colleagues raise several important considerations regarding the thalamic contribution to arousal. Their comments offer us an opportunity to clarify our findings in the context of the broader literature on the thalamus and its role in arousal. First, we should highlight the important distinction between what is evidence for the necessity of a structure for a particular function (in this case, maintaining conscious wakefulness) and what is evidence for the participation of that structure in modulating a function without being necessary for it. Our study design was aimed at evaluating whether the thalamus is necessary for maintaining a waking level of consciousness. This question is important if we wish to understand the human brain circuits underlying basic, conscious wakefulness. Many neural structures can modify cortical electroencephalographic (EEG) activity and, when stimulated, awaken subjects from sleep. These structures range from peripheral nerves to the spinal cord, brainstem and cerebral cortex, yet the distribution of regions that are actually necessary for maintaining wakefulness is quite small. We do not dispute the abundant evidence that thalamocortical function is necessary for a variety of cognitive processes that constitute, collectively, the “contents” of consciousness. If, however, the thalamus is necessary for maintaining wakefulness, one would expect that a lesion disrupting the entire thalamus would severely impair arousal, resulting in stupor or coma. Experimental lesion studies conducted in animals have consistently shown that the thalamus is not necessary for sustaining wakefulness. Ours is the first systematic analysis addressing this question in humans, and our findings are congruent with the animal studies; of 33 thalamic stroke patients, there were no patients with ischemia restricted to the thalamus that had a major effect on arousal. Furthermore, all patients with severely impaired arousal (coma or stupor) had clear-cut lesion extension into the midbrain and/or pons tegmentum. These findings are consistent with our own inpatient clinical experience and are consistent with a critical review of the literature, where comatose patients with “thalamic” strokes typically have ophthalmoplegia or other clear-cut clinical signs of brainstem involvement in a posterior-circulation stroke syndrome, or have direct imaging evidence of the “thalamic” stroke extending into the midbrain and/or pons tegmentum. The most parsimonious conclusion to be drawn from the existing literature, in our view, is that there are regions of the upper brainstem necessary for maintaining consciousness via projections to the forebrain, but that the thalamus itself does not play a necessary role in sustaining basic arousal. When making a claim like ours (that the thalamus itself is not necessary for basic, conscious wakefulness) it is important to set out criteria for what sort of evidence would falsify the claim. In our case, that evidence would include one or more patients after acute onset coma with high-resolution magnetic resonance diffusion imaging through the upper brainstem and thalamus, collected in the comatose state (preferably within 12–24 hours of onset), showing ischemia in the thalamus without extension into the midbrain or hypothalamus. We have sought such a case and to date, have not found it. However, if anyone has this evidence, we would be most interested in reviewing it and would revise our understanding of the arousal pathway accordingly. With regard to possible explanations for why we did not observe severe impairments in arousal in individuals with thalamic lesions, we largely disagree with the concerns listed by Dr Guaraldi and colleagues. Level of arousal in the first 12 hours of symptom onset from stroke as assessed by neurological examination is a valid approach for assessing the necessity of the thalamus for maintaining a basic level of arousal. A neurological examination is the best test for a wide variety of brain functions, including level of consciousness. We reviewed neurological examination information and included patients where there was explicit, unambiguous evidence of level of consciousness by a clinical examiner, typically a neurologist. This is a conservative criterion and a strength, not a weakness, of our methodology. We would not anticipate patients developing coma or stupor >12 hours after the onset of the stroke except due to swelling that compresses adjacent brain regions, and we do not see how EEG findings would aid the assessment. There are EEG correlates of impaired arousal, but their presence would not supersede neurological examination findings of conscious, waking behaviors. However, this is not to say that our approach could not be improved upon. For example, conducting level of consciousness assessments at regular intervals and with quantitative scales would benefit prospective studies addressing this topic, and prospective EEG monitoring could shed light on any changes in sleep and circadian function. Dr Guaraldi et al point to examples in the literature that they believe are in contrast to our results. However, none of the studies cited addresses the necessity of the thalamus for maintaining wakefulness. Rather, these studies show that the thalamus has a role in modifying sleep–wake states or generating sleep spindles, which are topics we make no claims about and our study design does not attempt to address. This type of evidence presented by Guaraldi et al—that the thalamus can modify arousal or promote sleep and sleep spindles—should not be confused or misconstrued as evidence for the necessity of the thalamus in arousal. Historically, this has occurred in the interpretation of electrical stimulation in the thalamus promoting cortical arousal, which formed the basis of the current dogma that the ascending arousal system includes the thalamus as a necessary structure. This view is predominant even today, despite experimental data challenging it. To close, we do not dispute that the thalamus has a role in modulating the arousal system, and recent experimental data in mice support this. This is in sharp contrast to a lack of data demonstrating that the thalamus is necessary for maintaining consciousness, although we and others should continue to search for such evidence and continually refine our understanding of the arousal circuitry in accordance with the data.