By Peter B. Forgacs, MD

Instructor in Neuroscience and Neurology, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medical College; and Instructor in Clinical Investigation, The Rockefeller University, New York

Dr. Forgacs reports no financial relationships relevant to this field of study.

SYNOPSIS: In this case-control, functional neuroimaging study, the authors developed a novel method to evaluate correlations between integrity of neural circuits involved in overt and covert motor behavior and apply the method to two patients: one with a dissociation of imaging-based vs bedside evidence of command following and one without.

SOURCE: Fernández-Espejo D, et al. A thalamocortical mechanism for the absence of overt motor behavior in covertly aware patients. JAMA Neurol 2015 Oct 19:1-9. doi: 0.1001/jamaneurol.2015.2614. [Epub ahead of print].

It is an increasingly well-described phenomenon that some severely brain-injured patients who appear to be in a vegetative or minimally conscious state at the bedside (collectively called disorders of consciousness [DOC]) may show evidence of preservation of higher cognitive capabilities detected by functional neuroimaging or electrophysiological methods. This syndrome of dissociation between clinically observable and covert motor behavior has gained widespread attention from clinicians, researchers, and the general public over the last 10 years, and recently has been named “cognitive motor dissociation” (CMD).1 Several independent studies2,3 involving large numbers of patients with DOC showed that approximately 10% of such patients may exhibit such dissociation between beside and functional neuroimaging findings. Fernandez-Espejo et al have taken an important step toward characterizing the different neural circuits that produce overt or covert motor behavior.

This case-control study involved 15 healthy volunteers and two patients with a history of severe brain injury and impaired consciousness. The authors used a mathematical modeling technique — dynamic causal modeling (DCM) — and applied it to functional magnetic resonance imaging (fMRI) signals to compare neural substrates of voluntary motor imagery and motor execution. In addition, diffusion tensor imaging (DTI) technique was also used in the patients to compare structural integrity of the neural fibers to those identified in DCM modeling. Their findings revealed that in healthy volunteers, motor execution was associated with excitatory coupling between the thalamus and primary motor cortex, but during a motor imagery task, coupling was not present. Furthermore, DTI analysis revealed selective disruption of these fibers in the one patient involved in the study with evidence of covert command following despite appearing to be in the vegetative state behaviorally. The other unconscious patient who had comparable injury and clinical history was able to exhibit goal-directed movements at the bedside, and had intact fibers between the thalamus and primary motor cortex as verified by the modeling and DTI fiber tracing.

COMMENTARY

This study addresses a very important but unresolved issue of assessing the underlying neuronal mechanism of the remarkable dissociation between lack of motor behavior with concordant preservation of high-level cognitive functions. It highlights the possible role of selective functional or structural loss of thalamo-cortical connections in cases of CMD, which frames the possibility of targeted restoration therapy in some cases of behaviorally unresponsive patients.

However, there are several weaknesses of the study. While their methods are validated in a single patient with CMD, the authors concluded that the findings of this study may be used as a possible biomarker for the absence of intentional movements in covertly aware patients. However, as the authors also agree, there may by significant individual structural and functional variations in localization of appropriate brain activity even in healthy volunteers; they could only identify suprathreshold activity using their DCM method in 60% (9 out of 15) of the healthy volunteers included in the study. These limitations may be even more pronounced and possibly restrict the generalization of their approach to severely brain-injured patients, who typically have significant structural damage and possible functional reorganization of brain activity during recovery. In addition, while their findings may explain the presence of CMD in a subset of patients, there are many other possible injury patterns that can produce loss of motor outflow without disruption of fibers from the ventrolateral thalamus to the primary motor cortex. These include injury of motor efferents at the level of upper brainstem as in the complete locked-in state. Alternatively, paucity of movements may be a result of upper motor neuron dysfunction leading to highly increased muscle tone and development of severe contractures, which is often the case in the chronic stages of severe brain injuries. Lastly, while findings of this study explain the lack of voluntary motor control, they cannot account for several clinical features that are also absent in patients who are mistakenly thought to be in a vegetative state based on bedside examination, such as visual fixation, visual pursuit, or vocalization. As the authors noted, currently there are no reliable models that account for all the dysfunctions seen in patients with CMD.

In summary, this study frames a highly important question about the neurobiological mechanisms of CMD and highlights the importance of thalamo-cortical connections. The authors proposed a model — selective disruption of fibers to the primary motor cortex from the ventrolateral thalamus with preservation of central thalamic outflow to the frontoparietal areas.4 They also propose that measurements of the selective integrity of these circuits may serve as a biomarker for CMD. However, while this paper involved two patients with DOC, previous studies using more conventional tools in a larger cohort of patients suggest that preservation of widespread cortical metabolism5 and global thalamo-cortical functions as reflected in sleep-wake EEG organization2 may be also used as a potential screening tool to identify preserved cognition.6 Nevertheless, if further studies will identify more patients with similar functional imaging results, the results of this study may be used to select patients for targeted restoration therapy, such as deep brain stimulation.

REFERENCES

  1. Schiff ND. Cognitive motor dissociation following severe brain injuries. JAMA Neurol 2015; Oct 19:1-3. doi: 10.1001/jamaneurol.2015.2899. [Epub ahead of print].
  2. Forgacs PB, et al. Preservation of electroencephalographic organization in patients with impaired consciousness and imaging-based evidence of command-following. Ann Neurol 2014;76:869-879.
  3. Monti MM, et al. Willful modulation of brain activity in disorders of consciousness. N Engl J Med 2010;362:579-589.
  4. Schiff ND. Recovery of consciousness after brain injury: A mesocircuit hypothesis. Trends Neurosci 2010;33:1-9.
  5. Stender J, et al. Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: A clinical validation study. Lancet Lond Engl 2014;384:514-522.
  6. Forgacs PB, et al. A proposed role for routine EEGs in patients with consciousness disorders. Ann Neurol 2015;77:185-186.