Thalamo-Prefrontal Connectivity Correlates with Early Command-Following After Severe Traumatic Brain injury

Recovery of consciousness after traumatic brain injury (TBI) is heterogeneous and difficult to predict. Structures such as the thalamus and prefrontal cortex are thought to be important in facilitating consciousness. We sought to investigate whether the integrity of thalamo-prefrontal circuits, assessed via diffusion tensor imaging (DTI), was associated with the return of goal-directed behavior after severe TBI. We classified a cohort of severe TBI patients (N = 25, 20 males) into Early and Late/Never outcome groups based on their ability to follow commands within 30 days post-injury. We assessed connectivity between whole thalamus, and mediodorsal thalamus (MD), to prefrontal cortex (PFC) subregions including dorsolateral PFC (dlPFC), medial PFC (mPFC), anterior cingulate (ACC), and orbitofrontal (OFC) cortices. We found that the integrity of thalamic projections to PFC subregions (L OFC, L and R ACC, and R mPFC) was significantly associated with Early command-following. This association persisted when the analysis was restricted to prefrontal-mediodorsal (MD) thalamus connectivity. In contrast, dlPFC connectivity to thalamus was not significantly associated with command-following. Using the integrity of thalamo-prefrontal connections, we created a linear regression model that demonstrated 72% accuracy in predicting command-following after a leave-one-out analysis. Together, these data support a role for thalamo-prefrontal connectivity in the return of goal-directed behavior following TBI.

Delta band activity contributes to the identification of command following in disorder of consciousness

The overt or covert ability to follow commands in patients with disorders of consciousness is considered a sign of awareness and has recently been defined as cortically mediated behaviour. Despite its clinical relevance, the brain signatures of the perceptual processing supporting command following have been elusive. This multimodal study investigates the temporal spectral pattern of electrical brain activity to identify features that differentiated healthy controls from patients both able and unable to follow commands. We combined evidence from behavioural assessment, functional neuroimaging during mental imagery and high-density electroencephalography collected during auditory prediction, from 21 patients and 10 controls. We used a penalised regression model to identify command following using features from electroencephalography. We identified seven well-defined spatiotemporal signatures in the delta, theta and alpha bands that together contribute to identify DoC subjects with and without the ability to follow command, and further distinguished these groups of patients from controls. A fine-grained analysis of these seven signatures enabled us to determine that increased delta modulation at the frontal sensors was the main feature in command following patients. In contrast, higher frequency theta and alpha modulations differentiated controls from both groups of patients. Our findings highlight a key role of spatiotemporally specific delta modulation in supporting cortically mediated behaviour including the ability to follow command. However, patients able to follow commands nevertheless have marked differences in brain activity in comparison with healthy volunteers.

Agitation Following Severe Traumatic Brain Injury Is a Clinical Sign of Recovery of Consciousness

Objective: Severe traumatic brain injury (sTBI) often results in disorders of consciousness. Patients emerging from coma frequently exhibit aberrant behaviors such as agitation. These non-purposeful combative behaviors can interfere with medical care. Interestingly, agitation is associated with arousal and is often among the first signs of neurological recovery. A better understanding of these behaviors may shed light on the mechanisms driving the return of consciousness in sTBI patients. This study aims to investigate the association between posttraumatic agitation and the recovery of consciousness.Methods: A retrospective chart review was conducted in 530 adult patients (29.1% female) admitted to Stony Brook University Hospital between January 2011 and December 2019 with a diagnosis of sTBI and Glasgow Coma Scale (GCS) ≤8. Agitation was defined as a Richmond Agitation Sedation Scale (RASS) > +1, or any documentation of equivalently combative and violent behaviors in daily clinical notes. The ability to follow verbal commands was used to define the recovery of consciousness and was assessed daily.Results: Of 530 total sTBI patients, 308 (58.1%) survived. Agitation was present in 169 of all patients and 162 (52.6%) of surviving patients. A total of 273 patients followed commands, and 159 of them developed agitation. Forty patients developed agitation on hospital arrival whereas 119 developed agitation later during their hospital course. Presence of in-hospital agitation positively correlated with command-following (r = 0.315, p < 0.001). The time to develop agitation and time to follow commands showed positive correlation (r = 0.485, p < 0.001). These two events occurred within 3 days in 54 (44.6%) patients, within 7 days in 81 (67.8%) patients, and within 14 days in 96 (80.2%) patients. In 71 (59.7%) patients, agitation developed before command-following; in 36 (30.2%) patients, agitation developed after command-following; in 12 (10.1%) patients, agitation developed on the same day as command-following.Conclusion: Posttraumatic agitation in comatose patients following sTBI is temporally associated with the recovery of consciousness. This behavior indicates the potential for recovery of higher neurological functioning. Further studies are required to identify neural correlates of posttraumatic agitation and recovery of consciousness after sTBI.

tDCS modulates effective connectivity during motor command following; a potential therapeutic target for disorders of consciousness

Transcranial direct current stimulation (tDCS) is attracting increasing interest as a potential therapeutic route for unresponsive patients with prolonged disorders of consciousness (PDOC). However, research to date has had mixed results. Here, we propose a new direction by directly addressing the mechanisms underlying lack of responsiveness in PDOC, and using these to define our targets and the success of our intervention in the healthy brain first. We used fMRI to characterise the effects of tDCS on brain activity and dynamics during command following, a task typically used to clinically assess awareness. Anodal tDCS over M1 and cathodal tDCS over the cerebellum led to long-range changes in thalamo-cortical coupling associated with the ability to produce motor responses to command. This suggests that tDCS may allow PDOC patients to overcome the motor deficits at the root of their reduced responsiveness, improving their rehabilitation options and quality of life as a result.

Cortical Function in Acute Severe Traumatic Brain Injury and at Recovery: A Longitudinal fMRI Case Study

Differences in the functional integrity of the brain from acute severe brain injury to subsequent recovery of consciousness have not been well documented. Functional magnetic resonance imaging (fMRI) may elucidate this issue as it allows for the objective measurement of brain function both at rest and in response to stimuli. Here, we report the cortical function of a patient with a severe traumatic brain injury (TBI) in a critically ill state and at subsequent functional recovery 9-months post injury. A series of fMRI paradigms were employed to assess sound and speech perception, command following, and resting state connectivity. The patient retained sound perception and speech perception acutely, as indexed by his fMRI responses. Command following was absent acutely, but was present at recovery. Increases in functional connectivity across multiple resting state networks were observed at recovery. We demonstrate the clinical utility of fMRI in assessing cortical function in a patient with severe TBI. We suggest that hallmarks of the recovery of consciousness are associated with neural activity to higher-order cognitive tasks and increased resting state connectivity.

A-174 Language Impairments Following Subcortical Infarct: An Aphasia Case Study

Objective Subcortical aphasia associated with internal capsule and adjacent structure lesions often involve impaired naming, grammatical but slow dysarthric speech, impaired syntactic comprehension, repetition impairments, and apraxia. Furthermore, neuropsychiatric disturbances, such as diminished motivation and emotional dysregulation are additionally expected given connections to frontal lobe circuits. Overall, the type and severity of aphasia varies following subcortical stroke and the pattern of symptoms associated with subcortical aphasia have not been fully explored. Method The present case is a 34-year-old right-handed African-American female who sustained an acute infarct involving the left splenium, thalamus, and internal capsule, who was evaluated at bedside. Results Upon initial exam, the patient was aphasic, exhibiting difficulties with expression, fluctuating comprehension and frequent paraphasic errors. Repetition and single-step command following were impaired and apraxia was evident. She demonstrated poor insight and awareness into her current deficits. She additionally demonstrated low motivation and mild emotional dysregulation with heightened anxiety and depression. During recovery she demonstrated improved comprehension, verbal output, and reduced emotionality. Conclusions Consistent with previous studies, this case demonstrates the extreme variability of subcortical lesions in their aphasic manifestations and may suggest that subcortical aphasias are generally milder than that of cortical aphasias with generally faster symptom recovery.