Deep Brain Stimulation and Cognition: Moving from Animal to Patient Nicholas D

Deep brain stimulation and cognition: moving from animal to patient Nicholas D. Schiff and Joseph J. Fins Purpose of review Introduction Brain electrical stimulation has been proposed as a strategy Historically, deep brain stimulation (DBS) in the to improve chronically impaired cognitive function. This brief thalamus, upper brainstem, and allied targets has been review places a small number of recent studies into a advanced as a method by which to restore consciousness broader historical context and identifies important to chronically unconscious patients following severe brain challenges for further development of this area of research. injuries, with limited evidence of effects. Although DBS Recent findings is an increasingly used mode of treatment for neuropsy- Behavioral improvements following severe brain injury with chiatric disorders, its underlying mechanisms of action in central thalamic deep brain stimulation were observed in these applications are not well characterized [1,2]. experimental studies conducted in rodents and a report on a Recent proposals have considered the application of single human. These findings suggest that this technique central thalamic DBS to improve cognitive function in warrants further study as a method to modulate cognitive conscious patients with severe cognitive disabilities. function in the setting of acquired brain injury. These efforts are closely linked to both the basic neuro- Summary physiologic functions of the DBS targets in forebrain This area of research offers the promise of new avenues to arousal regulation mechanisms and the underlying path- engage patients with nonprogressive brain injuries who, at ology of chronically impaired cognitive function following present, have rather limited therapeutic options. These severe brain injury. efforts, however, will require careful attention to issues of research and clinical ethics and study design. In this review we briefly outline the clinical and scientific foundations underpinning a recent study that demon- Keywords strated behavioral improvements with central thalamic arousal regulation, central thalamus, consciousness, stimulation in a single human subject who had remained consent in decisional incapacity, intralaminar thalamic in a minimally conscious state (MCS) for 6 years following nuclei, minimally conscious state a severe traumatic brain injury. These experimental and clinical data support further research to develop central Curr Opin Neurol 20:638–642. thalamic stimulation as an investigational therapeutic ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins. method. Such development, however, will require stringent efforts to develop patient selection criteria, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA study design, and ethical frameworks to ensure that this Correspondence to Nicholas D. Schiff, MD, Department of Neurology and line of enquiry remains aimed at achievable and desirable Neuroscience, Weill Medical College of Cornell University, 1300 York Avenue clinical goals. Room F610, New York, New York 10021, USA Tel: +1 212 746 2372; fax: +1 212 746 8532; e-mail: [email protected] Early experimental studies of deep brain Current Opinion in Neurology 2007, 20:638–642 stimulation and forebrain arousal Abbreviations The modern history of brain stimulation and arousal of DBS deep brain stimulation the forebrain begins with the studies conducted by MCS minimally conscious state MRF midbrain reticular formation Moruzzi and Magoun [3], who demonstrated that electrical stimulation of the brainstem reticular formation and ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins midline thalamus could produce desynchronization of the 1350-7540 electroencephalogram, similar to that seen in wakeful states. Based on these and other related experimental findings the concept of an ascending reticular activating system arose, with an essential role for the midbrain and intralaminar regions of the thalamus. A precise anatomic demonstration of a pathway from the midbrain reticular formation (MRF) to the intralaminar nuclei of the thalamus, as suggested by the original studies conducted by Moruzzi and Magoun, was identified three decades 638 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Deep brain stimulation Schiff and Fins 639 later by Steriade and Glenn [4] using electroanatomical in France, Japan, and the USA (further references available and single-unit recording methods. In a remarkable set of in the reports by Cohadon [10], Tsubokawa et al.[11] early behavioral experiments, Fuster [5] demonstrated and Hosobuchi and Yingling [12]), in which DBS was that direct electrical stimulation of the MRF improved applied to the centromedian thalamus and cervical spinal behavioral responsiveness and perceptual awareness in cord in a group of about 50 patients who were in the conscious monkeys, reducing reaction times and increas- vegetative state. It was as part of this series of studies that ing detection of near threshold stimuli. the most famous patient in this cohort, Terri Schiavo, was implanted with a deep brain stimulator in the posterior More recently, human imaging studies have shown that intralaminar nuclei of the right thalamus without effect activation of this pathway between MRF and intralaminar [12]. nuclei of the thalamus is associated with increasing levels of attentional focus during simple reaction time tasks [6]. Despite clear, clinically judged increases in arousal and At present, however, the nuclei within the central physiologic responses to brain stimulation in many thalamus are considered to play a more intermediate role patients, including changing of the frequency content of in arousal state control, with a primary role of activation the electroencephalogram and increases in cerebral meta- assigned to brainstem monoaminergic and cholinergic bolic rates measured using positron emission tomography, neuronal groups and neurons within the basal forebrain substantive clinical improvements were not identified in [7]. Importantly, inputs from the brainstem and basal the vegetative state patients treated with DBS. A small forebrain arousal system converge strongly on the intrala- number of patients with traumatic brain injury (studies minar and surrounding regions of the central thalamus [8], included anoxic, traumatic, and other etiologies) were suggesting that these neurons can be recruited through reported to exhibit significant improvement, but all of many types of arousal. these patients were studied within the known time frames for spontaneous recovery (all prior to 6 months). This Deep brain stimulation in chronically makes these observations uninterpretable, given that unconscious patients the studies were carried out without blinding, without Following these early experimental observations, clinical formal behavioral assessment of linkage of DBS to investigators in the late 1960s and 1970s began to consider behavioral changes, or with blocked periods of withdrawal electrical stimulation of the brainstem (tegmental of stimulation. More recently it has been acknowledged midbrain), thalamus (posterior intralaminar nuclei– that the patients did not fulfill the criteria for vegetative centromedian parafasicularis complex), and basal ganglia state [13] at the time of initiation of DBS; in retrospect, the (globus pallidus interna) for restoration of arousal and patients were judged to have exhibited evidence of beha- consciousness in chronically unconscious patients [9] vioral responsiveness consistent with MCS [14]. MCS (additional references are available in other reports patients have a longer time frame for significant functional [10–12]). Most patients included in these initial studies recovery [15], making spontaneous recovery even more had remained in conditions consistent with either near likely in these cases. brain death or vegetative state following severe traumatic brain injury. Although eye opening and some fragmentary The general failure of DBS when applied to vegetative movements were generally observed with electrical stimu- state patients can be understood within the context of the lation, consistent with an arousal effect, no examples of patients’ underlying pathology and the rationale for these recovery of sustained interactive behavior were noted; studies. Although vegetative state may be a transient neither were formal behavioral assessments conducted condition, patients remaining in vegetative state until to link DBS to clinical improvement. In a study of a single death have shown consistent neuropathology demonstrat- individual, conducted by Sturm et al. [9], electrical stimu- ing widespread death of thalamic and cortical (typically lation of the rostral thalamus was applied in a patient with less injured) neurons [16]. The application of DBS to focal injuries in the midbrain and thalamus following a patients with overwhelming brain injuries was motivated posterior circulation stroke. The patient was described to by the concept that DBS might support an overall state be in ‘some kind of unconsciousness which was neither a change (such as restoration of desynchronized patterns manifest coma nor a typical apallic syndrome [an older from the background of anesthesia-induced slow waves, term for vegetative state]’. In this patient, electrical stimu- as seen in the experiments conducted by Moruzzi and lation reportedly produced brief recovery of simple Magoun [3]),

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