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It is wonderful what we do as surgeons, but it is not natural to open the brain. If it was meant for us to open the brain, nature would have given us a window to just go ahead and open it up, but that’s not the case. How do we change people’s lives, how do we change their memories, their feelings, their features; It’s just unpredictable. We are at the very embryonic stages of learning about the brain, to be honest with you.
- Alfredo Quiñones-Hinojosa, M.D., Johns Hopkins University
Departamental Links
Advisors
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Roger L. Reep, PhD
department of physiological sciences
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hemispatial neglect is a devestating neurological condition in which a stroke on one side of the brain affects responding to visual, auditory, or somatosensory stimuli on the contralesional side. |
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The location of four key components of the network for directed attention: cortical areas AGm and PPC, dorsocentral striatum (DCS), and the lateral posterior thalamic nucleus (LP). A: Dorsal view of the left hemisphere of a rat brain, showing the planes of coronal sections depicted in panels C and D. Primary motor cortex is orange, somatosensory areas green, visual areas yellow, auditory areas purple. B: Lateral view of the left hemisphere. C: Coronal section at AP 0.0, withthe locations of AGm and DCS indicated. D: Coronal section at AP -3.7, with the locations of PPC and LP indicated. From: Reep and Corwin (2008) |
Major connections of the neural circuitry thought to mediate directed attention in rats. Arrows represent axonal projections between brain regions. The medial agranular (AGm) and posterior parietal (PPC) cortical areas are shown in green. Central and dorsal portions of the dorsocentral striatum (DCS) are shown in dark blue. Thalamic nuclei shown in red include: rostromedial component of VAL (ventral anterior – ventral lateral nuclear complex), MDl (lateral subnucleusof mediodorsal nucleus), VM (ventromedial nucleus), and the far medial, central and caudal components of the lateral posterior (LP) nucleus. The ventromedial portion of the substantia nigra pars reticulata (vmSNr) is shown in orange. Lateral and medial regions of the superior colliculus (SCollic) are shown in light blue. From: Reep and Corwin (2008) |
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 Hemispatial neglect is a neurological condition in which a stroke on one side of the brain affects responding to visual, auditory, or somatosensory stimuli on the contralesional side. These deficits in directed attention are not caused by primary sensory or motor dysfunction. In humans, neglect is most often caused by lesions in the posterior parietal lobes. A patient with neglect syndrome acts as if their contralesional side is nonexistent. This is characterized by the patient failing to recognize stimuli on the contralesional side, and only eating food on the ipsilesional side of a plate. Over 40% of all cases of brain damage caused by stroke result in neglect syndrome, which has a severe debilitating affect on patients and their families. Currently, there is no effective treatment for neglect.
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what is the specifc topography of the neuroantomy of hemispatial neglect? |
Dr. Reep and his colleagues have developed a rodent model of neglect in order to examine the neuroanatomical circuitry of neglect, and to develop possible pharmacological treatments. We collaborate with Dr. James Corwin from Northern Illinois University. Dr. Corwin’s lab conducts the behavioral and lesion studies on rats that has lead us to define what areas are responsible for neglect in the rat. In previous studies, the medial agranular (AGm), posterior parietal (PPC), and ventrolateral orbital cortices have been found to be analogous to cortical structures involved in neglect in the primate. In the rat, these cortical areas are extensively interconnected.
The dorsocentral striatum (DCS) is a very important region of interest in the circuitry of neglect. The DCS is a terminating site for neurons projecting from AGm. We have shown that lesions in  DCS cause neglect that cannot be recovered from. Consequently, DCS is the focus of efforts to promote recovery from neglect produced by unilateral cortical lesions by inducing neural sprouting. Integrety of DCS is required in order for recovery to occur.
We now believe that the thalamic lateral posterior nucleus (LP) is another center of activity in the circuitry of neglect. LP has extensive reciprocal connections with AGm and PPC, and with DCS. It also is connected to the superior colliculus which is a major region for directed motor activation. I have been focusing my research on defining the specific topography of connections in LP, and have found that the projections to AGm and PPC are significantly segregated, such that fmLP (far medial LP) projects to caudal AGm whereas other portions of LP project to PPC. In addition, only fmLP projects to DCS.
The above considerations suggest that fmLP is a critical node in the circuitry for neglect and recovery, due to its connections with AGm and DCS. I have been studying the connections of LP to AGm and PPC using fluorescent retrograde tracers in order to determine the specific pathway for directed attention. The basic methodological paradigm for neuroanatomical tracers is to perform a craniotomy to expose the brain surface, an injection of the tracer into a specific region, and subsequent visualization of the tissue under a microscope after the brain is removed. Fluorescently labeled probes are used in order to allow multiple injections of differently colored tracers into the same animal in order to compare the topography of different regions. In order to perform these procedures, I have become licensed to perform aseptic survival brain surgeries on rats, and have done over 70 surgeries to date.
  Recently, I have found that the cingulate cortex (CG1) is also important in the circuitry of neglect. CG1 is located medially to AGm in the cortex. I found that the dorsal region of fmLP projects more to CG1 but the ventral region of fmLP projects more to AGm (Figure 1). These findings are important, because the cingulate cortex is thought to be involved in attentional processes in humans. In the rat, this LP-CG1 pathway also projects to the same area of DCS that is thought to produce the most severe neglect symptoms.
Additionally, I have a research interest in the chemistry of the neural tracers we use: dextran amines and cholera toxin (CTB). I designed a study that examined the effects of modifying the buffer chemistry that changes the route of transport of dextran amines. I then compared these findings to the newly available fluorescent conjugates of CTB, and found that CTB is a much better retrograde tracer than dextran amine. Ultimately, I have strived to help develop and modify improved brain imaging methodologies, and have recently submitted a first-authored article to a major journal.
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why is this important? |
Due to the complex multimodal paradigm of attentional defecits in neglect, it is of extreme importance to define the specific neuroanatomical connection involved. The findings not only increase our knowledge for the circuitry of neglect, but also the general circuitry for directed attention. |
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Futher Readings |
Kamishina H, Yurcisin GH, Corwin JV, Reep RL. Striatal projections from the rat lateral posterior thalamic nucleus. Brain Research 2008;1204:24-39.
Reep RL, Corwin JV. Posterior parietal cortex as part of a neural network for directed attention in rats. Neurobiology of Learning and Memory 2008.
Cheatwood JL, Corwin JV, Reep RL. Overlap and interdigitation of cortical and thalamic afferents to dorsocentral striatum in the rat. Brain Research 2005;1036:90-100.
Cheatwood JL, Reep RL, Corwin JV. The associative striatum: cortical and thalamic projections to the dorsocentral striatum in rats. Brain Research 2003;968:1-14.
Reep RL, Corwin JV, Cheatwood JL, Van Vleet TM, Heilman KM, Watson RT. A Rodent Model for Investigating the Neurobiology of Contralateral Neglect. Cognitive & Behavioral Neurology 2004;17:191-4.
Van Vleet TM, Heldt SA, Corwin JV, Reep RL. Infusion of apomorphine into the dorsocentral striatum produces acute drug-induced recovery from neglect produced by unilateral medial agranular cortex lesions in rats. Behavioural Brain Research 2003;143:147-57.
Karnath H-O, Himmelbach M, Rorden C. The subcortical anatomy of human spatial neglect: putamen, caudate nucleus and pulvinar. Brain 2002;125:350-60.
Van Vleet TM, Burcham KJ, Corwin JV, Reep RL. Unilateral destruction of the medial agranular cortical projection zone in the dorsocentral striatum produces severe neglect in rats. Psychobiology 2000;28:57-66.
Reep RL, Corwin JV. Topographic organization of the striatal and thalamic connections of rat medial agranular cortex. Brain Research 1999;841:43-52.
Reep RL, Chandler HC, King V, Corwin JV. Rat posterior parietal cortex: topography of corticocortical and thalamic connections. Experimental Brain Research 1994;100:67-84.
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