Case Study 33 A Full Caudal Rostral Periaqueductal Gray PAG Lesion Akinetic Mutism and the Emptying Out of Consciousness2

This man in his early thirties was found unresponsive and in a deep stupor. Initial structural imaging with CT showed a large expanding mass lesion of the mid-brain. The patient was treated with steroids to reduce swelling and had a marked, rapid regression of the lesion in the midbrain. After the lesion resolved, his stupor improved and he was then found to demonstrate a classic akinetic mute state: vigilant appearance, relatively intact ocular tracking, some quite limited spontaneous movements of the left arm with stimulation, but following no commands or showing any reliable signs of human social interaction, affect, speech output, higher cognitive

2Case materials from Schiff (personal communication).

functions, or any motivated behavior. An MRI (magnetic resonance imaging) then showed high signal abnormalities in the midbrain, pretectum around the aqueduct, and some involvement into the paramedian thalamus on the left, probably affecting various midline and intralaminar systems, but no other discernible structural pathology. A SPECT (single-photon emission computed tomography) scan showed diffuse hypometabolism widely affecting association cortices bilaterally, including frontal, parietal, and temporal association cortices, consistent with the supposition that higher cognitive and executive functions were all off-line. The patient died several months later secondary to pneumonia, but without any clinical change in his neurological or akinetic mute mental status. At autopsy, pathology confirmed a lymphoma that had regressed through and subsequently destroyed the paramedian tegmental mesen-cephalon, tracked through the aqueduct to the thalamus, extending partially into the anterior intralaminar region on left side, with the preservation of the right intralaminar region possibly allowing for some apparently purposeless movements of the left upper extremity.

As far as we know, no other case of full caudal-rostral PAG involvement (with relative sparing of the other mesodiencephalic areas) has been documented by this much structural imaging, functional imaging, and neuropathological data. This case is fully consistent with animal work in which extensive caudal-rostral lesions of PAG consistently produce a severe akinetic mute state with little progress toward any resolution or generation of visible affect or spontaneous motivated behavior. The PAG receives telencephalic projections restricted to limbic and paralimbic systems such as the central nucleus of amygdala and anterior paleocortices (cingulate and orbital frontal), and there is a close relationship between this structure and the largely DA-mediated seeking system (Panksepp, 1998). PAG has extensive reciprocal projections to these systems and also to the hypothalamus, multiple monoamine nuclei, and the thalamic ILN systems, the posterior ILN group in particular (centromedian/parafascicular).

Animal work suggests that PAG plays an essential role in making emotion an active motoric process, as most prototypic affective behaviors (fleeing, freezing, copulating, affective vocalizations, possibly many attachment behaviors, etc.) appear to be organized by PAG-hypothalamic-brainstem motor system networks. Its role in the complexity of more cognized human affective states is still poorly outlined empirically, but it may be responsible (by virtue of its extensive reticular and intralaminar connectivities) for widely influencing the thalamocortical system consonant with underlying affective states, thus being in a position to "gate" or restrict state space of the thala-mocortical system (see Watt, 2000, for summary). This gating function might be an important substrate for basic aspects of prototype strong emotion, such as how playful behaviors are not available when we are angry.

Observation and discussion of AKM often begs the question "well, aren't these patients still conscious?" Lesser versions of the syndrome seen in more limited cases of bilateral cingulate disease typically show sufficient recovery that patients are later able to report experiencing events but lacking desire or intention. In some cases, bilateral cingulate patients will even respond to verbal inquiry, particularly if supplementary motor areas are spared. This leads to a deepening of the suspicion that AKM is not a

"true" disease of consciousness. These milder versions of AKM appear to offer evidence of the independence of consciousness from an emotional bedrock, and that the former can exist without the latter. Our somewhat different conclusion is that lesser versions of AKM (classically associated with bilateral cingulate disease) may allow some phenomenal content, while the more severe versions (associated with very extensive lesions of PAG, or ventral tegmentum area (VTA), and some subcortical bilateral basal ganglia presentations) may show a virtual "emptying out" of consciousness. In these cases, events may be virtually meaningless and simply don't matter anymore. It may be an essential requirement that stimuli have at least some potential affective significance in order to gain access to the conscious workspace. In extensive PAG lesions, consciousness thus may be essentially "grayed out." This suggests that these more severe AKM patients live in a kind of strange, virtually unfathomable netherworld close to the border of a persistent vegetative state. With the patient discussed above, and in the few other closely studied cases with extensive PAG lesions, the clinical condition of akinetic mutism does not appear to resolve. In contrast, the akinetic mutism from an ILN lesion (Case study 3.2) is almost always temporary.

Our taxonomy of disorders of consciousness emphasizes their graded, progressive nature and eschews an all-or-nothing conceptualization. While intuitively appealing, an all-or-nothing picture of consciousness provides a limited basis for heuristic empirical study of the underpinnings of consciousness from a neural systems point of view, as compared to a graded or hierarchical one that emphasizes the core functional envelopes of emotion, intention, and attention. From this vantage point, akinetic mutism is a deeply informative syndrome, as it provides clues to the neural "minimums" for motivated behavior and emotion in the human brain. Additionally, it bears emphasis that the syndrome of akinetic mutism potentially provides clues to psychiatry about neural substrates of other related, but lesser, apathy states, such as those seen in severe retarded depression, schizophrenia, catatonia, and the like.

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