https://www.pnas.org/content/118/31/e2111268118


Dopaminergic modulation of human consciousness via default mode network connectivity

 View ORCID ProfileBrian L. Edlow

 See all authors and affiliationsPNAS August 3, 2021 118 (31) e2111268118; https://doi.org/10.1073/pnas.2111268118

Decades of preclinical studies indicate that dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain modulate animal behavior and cognition (1). The role of dopaminergic VTA neurons in wakefulness, and hence consciousness, emerged more recently from VTA stimulation experiments utilizing pharmacologic (2, 3), electrophysiologic (4), optogenetic (5, 6), and chemogenetic (7) methods, as well as behavioral experiments in dopamine knockout mice (8). Yet, confirmation of VTA modulation of human consciousness has until now been elusive—inferred from pharmacologic studies of dopaminergic therapies (9) and positron emission studies of dopamine receptor dynamics (10), but unconfirmed due to a lack of suitable techniques for measuring VTA function in humans. This absence of a translational link between animal and human VTA function has hindered the construction of a comprehensive subcortical–cortical connectivity model of human consciousness and impeded the development of new therapies to promote recovery of consciousness in patients with severe brain injuries (11).

In PNAS, Spindler et al. report groundbreaking results from complementary observational and interventional studies that shed light on VTA modulation of human consciousness, bridging the gap between animal and human VTA research (12). In a series of resting-state functional MRI experiments performed in healthy volunteers undergoing propofol-induced sedation (n = 24), patients with chronic disorders of consciousness (DoC) caused by severe brain injuries (n = 22), and patients with traumatic brain injury treated with methylphenidate (n = 12), Spindler et al. (12) provide convergent evidence that the subcortical VTA modulates human consciousness via connectivity with the cortical default mode network (DMN). Although VTA neurons connect with multiple regions of the cerebral cortex via monosynaptic and polysynaptic pathways that traverse the mesocortical, mesolimbic, and nigrostriatal bundles (13), the experiments here focus on VTA connectivity with the precuneus/posterior cingulate cortex (PCu/PCC), a well-established “hub node” of the …

1Email: bedlow@mgh.harvard.edu.

References

    1.  M. Morales, 
    2. E. B. Margolis
    , Ventral tegmental area: Cellular heterogeneity, connectivity and behaviour. Nat. Rev. Neurosci. 18, 73–85 (2017).CrossRefPubMedGoogle Scholar
    1.  K. Solt et al
    ., Methylphenidate actively induces emergence from general anesthesia. Anesthesiology 115, 791–803 (2011).CrossRefPubMedGoogle Scholar
    1.  J. D. Kenny, 
    2. N. E. Taylor, 
    3. E. N. Brown, 
    4. K. Solt
    , Dextroamphetamine (but not atomoxetine) induces reanimation from general anesthesia: Implications for the roles of dopamine and norepinephrine in active emergence. PLoS One 10, e0131914 (2015).CrossRefPubMedGoogle Scholar
    1.  K. Solt et al
    ., Electrical stimulation of the ventral tegmental area induces reanimation from general anesthesia. Anesthesiology 121, 311–319 (2014).CrossRefPubMedGoogle Scholar
    1.  N. E. Taylor et al
    ., Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia. Proc. Natl. Acad. Sci. U.S.A. 113, 12826–12831 (2016).Abstract/FREE Full TextGoogle Scholar
    1.  A. Eban-Rothschild, 
    2. G. Rothschild, 
    3. W. J. Giardino, 
    4. J. R. Jones, 
    5. L. de Lecea
    , VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors. Nat. Neurosci. 19, 1356–1366 (2016).CrossRefPubMedGoogle Scholar
    1.  Y. Oishi et al
    ., Activation of ventral tegmental area dopamine neurons produces wakefulness through dopamine D2-like receptors in mice. Brain Struct. Funct. 222, 2907–2915 (2017).CrossRefPubMedGoogle Scholar
    1.  R. D. Palmiter
    , Dopamine signaling as a neural correlate of consciousness. Neuroscience 198, 213–220 (2011).CrossRefPubMedGoogle Scholar
    1.  J. T. Giacino et al
    ., Placebo-controlled trial of amantadine for severe traumatic brain injury. N. Engl. J. Med. 366, 819–826 (2012).CrossRefPubMedGoogle Scholar
    1.  E. A. Fridman, 
    2. J. R. Osborne, 
    3. P. D. Mozley, 
    4. J. D. Victor, 
    5. N. D. Schiff
    , Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury. Brain 142, 1887–1893 (2019).PubMedGoogle Scholar
    1.  B. L. Edlow et al
    ., Personalized connectome mapping to guide targeted therapy and promote recovery of consciousness in the intensive care unit. Neurocrit. Care 33, 364–375 (2020).Google Scholar
    1.  L. R. B. Spindler et al
    ., Dopaminergic brainstem disconnection is common to pharmacological and pathological consciousness perturbation. Proc. Natl. Acad. Sci. U.S.A. 118, e2026289118 (2021).Abstract/FREE Full TextGoogle Scholar
    1.  L. Yetnikoff, 
    2. H. N. Lavezzi, 
    3. R. A. Reichard, 
    4. D. S. Zahm
    , An update on the connections of the ventral mesencephalic dopaminergic complex. Neuroscience 282, 23–48 (2014).CrossRefPubMedGoogle Scholar
    1.  A. Vanhaudenhuyse et al
    ., Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients. Brain 133, 161–171 (2010).CrossRefPubMedGoogle Scholar
    1.  K. C. R. Fox, 
    2. B. L. Foster, 
    3. A. Kucyi, 
    4. A. L. Daitch, 
    5. J. Parvizi
    , Intracranial electrophysiology of the human default network. Trends Cogn. Sci. 22, 307–324 (2018).CrossRefPubMedGoogle Scholar
    1.  R. L. Buckner, 
    2. L. M. DiNicola
    , The brain’s default network: Updated anatomy, physiology and evolving insights. Nat. Rev. Neurosci. 20, 593–608 (2019).CrossRefPubMedGoogle Scholar
    1.  M. P. van den Heuvel, 
    2. O. Sporns
    , Network hubs in the human brain. Trends Cogn. Sci. 17, 683–696 (2013).CrossRefPubMedGoogle Scholar
    1.  B. L. Edlow, 
    2. J. Claassen, 
    3. N. D. Schiff, 
    4. D. M. Greer
    , Recovery from disorders of consciousness: Mechanisms, prognosis and emerging therapies. Nat. Rev. Neurol. 17, 135–156 (2021).Google Scholar
    1.  P. O. Jenkins et al
    ., Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging. Brain 142, 2367–2379 (2019).Google Scholar
    1.  M. Boly et al
    ., Are the neural correlates of consciousness in the front or in the back of the cerebral cortex? Clinical and neuroimaging evidence. J. Neurosci. 37, 9603–9613 (2017).Abstract/FREE Full TextGoogle Scholar
    1.  J. J. Provencio et al
    ., The Curing Coma Campaign: Framing initial scientific challenges—Proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting. Neurocrit. Care 33, 1–12 (2020).CrossRefGoogle Scholar
    1.  B. L. Edlow et al
    ., Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J. Neuropathol. Exp. Neurol. 71, 531–546 (2012).CrossRefPubMedGoogle Scholar
    1.  M. Bianciardi, 
    2. S. Izzy, 
    3. B. Rosen, 
    4. L. L. Wald, 
    5. B. L. Edlow
    , Location of subcortical microbleeds and recovery of consciousness after severe traumatic brain injury. Neurology 97, e113–e123 (2021).Google Scholar
    1.  A. L. Nolan et al
    ., Tractography-pathology correlations in traumatic brain injury: A TRACK-TBI study. J. Neurotrauma 38, 1620–1631 (2021).

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s