Neglect as a consequence of right brain damage has been recognized at least since J. Hughlings Jackson’s 1876 case report . It was later appreciated that impairment in brain functional connectivity and resulting brain network dysfunction (‘connectopathy’, ‘disconnection syndrome’) underlies hemispatial neglect, a common sequela of right hemispheric stroke [2, 3]. A variety of bedside tests have been found useful as a measure of hemispatial neglect, including the Clock-Drawing Test . The signature pattern of hemispatial neglect seen after right brain damage with the Clock-Drawing Test is a clock face, drawn from memory, lacking numerals in its left half, which has been termed neglect of the left hemispace  (Fig. 1a).
Advanced brain imaging methods, including functional magnetic resonance and positron emission tomography (PET), allow the in vivo assessment of functional connectivity and neuroinflammation, respectively. These imaging methods have expanded our understanding of post-stroke neuroinflammation. A growing body of evidence suggests that stroke may result in persistent global brain inflammation and that neuroinflammation may impair brain functional connectivity [2, 3, 6,7,8,9,10,11,12]. Neuroinflammation after stroke involves microglial activation [9, 12]. Elevated levels of the cytokine tumor necrosis factor (TNF) in the brain have been implicated in a wide range of brain disorders .
Elevated levels of TNF may adversely affect brain network function because TNF’s normal physiological roles include its function as a neuromodulator and gliotransmitter that modulates synaptic scaling and synaptic strength, and regulates the tripartite synapse [9, 11, 14, 15]. Biologics targeting TNF have become one of most widely used therapeutics in modern medicine. One such human therapeutic is etanercept, a recombinant fusion protein that potently and selectively inhibits the biological activity of TNF. In basic science models, etanercept has been found to reduce microglial activation and ameliorate neurological dysfunction [7,8,9,10,11, 16]. More recently, in addition to its ability to rapidly reduce chronic post-stroke neurological dysfunction when administered by perispinal injection, etanercept was shown to improve neurological outcomes in six different experimental models of stroke [9, 11, 16].
In contrast to its rapid brain effects when injected perispinally, etanercept has difficulty crossing the blood–brain barrier in therapeutic quantities when administered systemically [9, 11, 14, 16, 17]. To avoid the trauma associated with invasive methods of brain delivery, such as intracerebroventricular injection, a new method of drug delivery was needed to facilitate the use of etanercept for brain disorders [9, 11, 14,15,16,17]. Perispinal administration was designed as a novel method to enhance delivery of etanercept and other large molecules to the brain via the cerebrospinal venous system (CSVS) (Fig. 2) [6, 9, 11, 14,15,16,17,18].
The CSVS consists of the interconnected cerebral and spinal venous systems, a unique, large capacity, essentially valveless venous network within which bi-directional blood flow occurs, including retrograde blood flow from the spinal venous blood into the brain [11, 16, 18]. Venous drainage of the anatomical region posterior to the spine is accomplished by the external vertebral venous plexus, the most superficial component of the CSVS [11, 16, 18]. The external vertebral venous plexus drains into the internal vertebral venous plexus, which itself drains, and drains into the cerebral venous system [11, 16, 18]. Perispinal injection of etanercept delivers etanercept into the catchment area of the external vertebral venous plexus, thereby enabling etanercept to bypass the blood–cerebrospinal fluid barrier and reach the brain [6,7,8,9,10,11, 13,14,15,16,17,18,19].
In an animal model, perispinal administration has been shown to rapidly deliver radiolabeled etanercept into the choroid plexus and cerebrospinal fluid using PET (Fig. 3) .
More recently, in another animal model, perispinal administration of a TNF antibody was shown to deliver the antibody into the choroid plexus and to have favorable brain effects, alleviating the sensory and affective components of neuropathic pain .
Perispinal etanercept is an emerging treatment for chronic, post-stroke neurological dysfunction, that has been used clinically for more than 8 years and is currently the subject of multiple randomized, placebo-controlled trials underway or in development [7,8,9, 11, 14]. In stroke, the widespread pattern of rapid neurological improvement seen after perispinal etanercept has been attributed to improvement in functional connectivity due to neutralization of excess TNF . Rapid improvement in clock drawing in a patient with Alzheimer’s disease after perispinal etanercept has previously been reported, but improvement in the Clock-Drawing Test in post-stroke patients after perispinal etanercept has not yet been published .