E-Letter responses to:

reports: Marcello Massimini, Fabio Ferrarelli, Reto Huber, Steve K. Esser, Harpreet Singh, and Giulio Tononi Breakdown of Cortical Effective Connectivity During Sleep Science 2005; 309: 2228-2232 [Abstract] [Full text] [PDF]

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Published E-Letter responses:

Re: Cortical Effective Connectivity During Sleep: Not a Matter of Stimulus Intensity

Giulio Tononi, Marcello Massimini   (23 March 2007)

Cortical Effective Connectivity During Sleep: A Matter of Stimulus Intensity?

Ramin Khatami, Farid Salih   (19 April 2006)

Re: Cortical Effective Connectivity During Sleep: Not a Matter of Stimulus Intensity 23 March 2007
Giulio Tononi Department of Psychiatry, University of Wisconsin-Madison, Marcello Massimini Respond to this E-Letter: Re: Re: Cortical Effective Connectivity During Sleep: Not a Matter of Stimulus Intensity	In their letter, Khatami and Salih wonder whether the lack of propagation of TMS-evoked activity that we measured with high-density EEG during NREM sleep could be due to reduced cortical excitability rather than to a breakdown of cortical effective connectivity. Since the threshold for evoking responses in hand muscles through TMS of motor cortex increases by about 5 to 10% during NREM sleep, Khatami and Salih suggest that the stimulation intensity used to probe cortical circuits should be corrected for the changes in motor threshold (MT). However, relying on MT to evaluate cortical excitability is problematic, since motor responses are influenced by sleep-related changes in the excitability of spinal motoneurons. Specifically, during NREM sleep, spinal motoneurons are hyperpolarized (1) and the spinal H-reflex is reduced by 20 to 30% (2, 3). Therefore, in our study we relied directly on the cortical (EEG) response to TMS by selecting the minimum stimulation intensity that yielded a statistically significant TMS-evoked potential in all states of vigilance. Regardless, as shown in the figure below, the breakdown of effective connectivity during NREM sleep cannot be explained by insufficient stimulation intensities. Here, TMS was delivered during NREM sleep at 90, 130, and 160% of MT in a subject who underwent a full dose-response curve without waking up (same experiment as in Fig. S3 of the original Report). The low-frequency response typical of NREM sleep increased in amplitude (up to 30 microvolts) with increasing stimulation intensity. However, at all intensities, the maximal TMS-induced response remained confined to the stimulated area and failed to trigger any specific pattern of long-range activation. References 1. M. H. Chase, S. H. Chandler, Y. Nakamura, J. Neurophysiol. 44, 349 (1980). 2. R. Hodes, W. C. Dement, Electroenceph. Clin. Neyrophysiol. 17, 617 (1964). 3. L. Mercier , R. T. Pivik, J. Clin. Neuropsychol. 5, 321(1983).
Cortical Effective Connectivity During Sleep: A Matter of Stimulus Intensity? 19 April 2006
Ramin Khatami, MD Department of Neurology , University Hospital, Frauenklinikstr. 26; Zurich, Switzerland, Farid Salih Respond to this E-Letter: Re: Cortical Effective Connectivity During Sleep: A Matter of Stimulus Intensity?	In their Report (“Breakdown of Cortical Effective Connectivity during Sleep,” 30 Sept 2005), M. Massimini et al. try to explain the fading of consciousness in the transition from wakefulness to NREM-sleep by a breakdown of cortical effective connectivity and the inability to integrate information. Using transcranial magnetic stimulation (TMS) combined with high-density EEG they observed an enhanced activation at the stimulation site but a loss of propagation of subsequent waves to connected areas when subjects fell asleep. As single pulse TMS below motor threshold has been equally applied in all states of vigilance we are concerned about parts of their interpretation. At sub-threshold intensities, TMS activates cortico-cortical interneurons and/or thalamo-cortical neurons alone (1), whereas TMS beyond threshold leads to transsynaptic activation of principal cortical cells (such as pyramidal cells). We have previously shown that motor threshold changes in NREM-sleep (2). Hence, stimulus intensities have to be adjusted in each state of vigilance when qualitative differences of cortex functioning between sleep and wakefulness is aimed to be tested (3). Likewise, the existence of a vigilance-dependent breakdown of cortex functions (such as cortical effective connectivity) should be independent of stimulus intensities. The loss of propagation of stimulus-induced activity to connected areas during NREM-sleep as shown by Massimini et al. might therefore only reflect inappropriate excitation of reorganized cortico-cortical cell populations (4) rather than a breakdown of effective information transmission. Inappropriate excitation of cortico-cortical neurons might also account for the stronger initial response seen at stimulation site. Even in wakefulness, numerous cortical areas reveal stronger excitability of cortico-cortical neurons at lower sub-threshold intensities when compared to higher intensities (5). In using the same stimulation intensity as for wakefulness, the question remains open whether cortical effective connectivity is really broken down or rather reorganized when we fall asleep. References 1. Rossini P. M. et al., Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: Basic principles and procedures for routine clinical application, Report of an IFCN committee, Electroencephalogr. Clin. Neurophysiol. 1994; 91:79-92. 2. Grosse P., Khatami R., Salih F., Kuhn A., Meyer B. U., Corticospinal excitability in human sleep as assessed by transcranial magnetic stimulation, Neurology 2002;59:1988–1991. 3. Salih F., Khatami R., Steinheimer S., Hummel O., Kuhn A., Grosse P., Inhibitory and excitatory intracortical circuits across the human sleep-wake cycle using paired-pulse TMS, J. Physiol. 2005;565:695-701. 4. Steriade M., Timofeev I., Grenier F.. Natural waking and sleep states: A view from inside neocortical neurons, J. Neurophysiol. 2001; 85:1969–1985. 5. Chen R., Tam A., Butefisch C., Corwell B., Ziemann U., Rothwell J. C., Cohen L. G., Intracortical inhibition and facilitation in different representations of the human motor cortex, J. Neurophysiol. 1998;80:2870- 2881.