Current controversies in states of chronic unconsciousness

Coma resulting from brain injury or illness usually is a transient state. Within a few weeks, patients in coma either recover awareness, die, or evolve to an eyes-open state of impaired responsiveness such as the vegetative or minimally conscious state. These disorders of consciousness can be transient stages during spontaneous recovery from coma or can become chronic, static conditions. Recent fMRI studies raise questions about the accuracy of accepted clinical diagnostic criteria and prognostic models of these disorders that have far-reaching medical practice and ethical implications (Full text).

Update: diagnosis, treatment, and prognosis of glioma

As the profession of neurology becomes increasingly subspecialized, it becomes more and more difficult for general neurologists to feel comfortable with every category of disease. At no time is this felt more keenly than when an imaging procedure has been performed on a patient for a seizure, headache, or focal neurologic complaint and a brain tumor is discovered. In contrast to consulting with a patient with a movement disorder or neuromuscular disease, there is no time to craft the discussion and discuss a differential diagnosis. As with demyelinating disease or stroke, the scan result dictates an immediate conversation with the patient, but in contrast to those disorders this takes place from the perspective of a provider who understands that the eventual outcome for the patient is likely to be guarded. How to give that message with tact, candor, and some optimism could be the sole topic of this article but, instead, we focus on 5 new ideas that are changing the management of brain tumor patients in the hopes that these points might prove useful during those times (Full text).

Update: Therapeutic options in multiple sclerosis

Care of the patient with multiple sclerosis (MS) is becoming increasingly complex, with new symptomatic therapies (e.g., dalfampridine), enhanced use of disease-modifying therapies that are potentially both more efficacious and more risky (e.g., natalizumab, rituximab) than “standard” immunomodulators, the advent of oral disease-modifying therapies (DMTs) (e.g., fingolimod, cladribine, teriflunomide, laquinimod), and the possibility of regenerative or reparative therapies (e.g., stem cells, neuroprogenitor cells, antibodies to leucine-rich repeat and immunoglobulin (Ig) domain containing NOGO receptor interacting protein-1, i.e., anti-LINGO therapies). All of this is happening in the context of a suggestion that MS may fundamentally result from aberrant venous flow, so-called chronic cerebrospinal venous insufficiency (CCSVI), and a similarly fundamental pathologic discussion of the relationship between inflammation and degeneration over time in patients with MS. Noting the difficulty of choosing among many options, we present discussions of 5 new topics relevant to patients with MS and their neurologists in 2010 (Full text).

Update in Stroke treatment and prevention

It has been almost 15 years since the publication of the landmark National Institute of Neurological Disorders and Stroke tissue plasminogen activator (NINDS-tPA) trial. The findings of the NINDS-tPA trial soon led to Food and Drug Administration (FDA) approval for IV alteplase (tPA) in the treatment of acute ischemic stroke (AIS) that transformed the way neurologists approach this devastating disease. Unfortunately, 15 years removed from the NINDS-tPA trial, IV tPA remains the only FDA-approved drug for the treatment of AIS. Although no major clinical breakthrough has occurred in the AIS treatment front, newer trials have increased the spectrum of patients who can be treated, but failed to find better lytic drugs or ways to identify treatable patients using advanced imaging. Major advancements have transpired in the arena of stroke prevention, especially in endovascular therapy and management of atrial fibrillation (AF). This article aims to summarize 5 new topics in stroke treatment, prevention, and poststroke care that have or will soon affect clinical treatment of stroke patients, and to offer critiques and commentary on how the results of the trials presented can be applied to the care of individual stroke patients (Full text).

Current understanding and management of Parkinson disease: Five new things

PubMed query for “Parkinson disease” yields more than 2,000 articles per year for each of the last 5 years. That is a daunting pile of bedside reading for even the most diligent neurologist. This review highlights 5 emerging topics that are changing our current understanding and management of Parkinson disease (PD). When using the term PD, we mean Lewy body parkinsonism as defined by the clinical criteria of the United Kingdom Parkinson's Disease Society Brain Bank. Other parkinsonian syndromes, such as progressive supranuclear palsy and multiple system atrophy, are beyond the scope of this review (Full text).

Approach to acute or subacute myelopathy

Improved understanding of the differential diagnosis and improved investigative techniques, particularly neuroimaging and serologic testing, have facilitated the diagnosis of patients with acute and subacute myelopathy and reduced the proportion of patients who are labeled as having “idiopathic transverse myelitis.” Additionally, these advances have identified subgroups of patients in whom progression of deficit or future relapses are anticipated, allowing intervention and prophylaxis as appropriate. However, early management remains empiric and consists of high-dose corticosteroids for most patients. In the event of an inadequate response to corticosteroids or a subsequent atypical course, further investigations to detect diagnoses other than “transverse myelitis” should be considered and additional treatments, such as plasmapheresis, may be appropriate. Individualized diagnosis and treatment is more feasible now than in the past (Full text).   

Neurology November 1, 2010 vol. 75 no. 18 Supplement 1 S2-S8

Insular cortex

The insular taste cortex contributes to odor qualiting coding
Despite distinct peripheral and central pathways, stimulation of both the olfactory and the gustatory systems may give rise to the sensation of sweetness. Whether there is a common central mechanism producing sweet quality sensations or two discrete mechanisms associated independently with gustatory and olfactory stimuli is currently unknown. Here authors used fMRI to determine whether odor sweetness is represented in the piriform olfactory cortex, which is thought to code odor quality, or in the insular taste cortex, which is thought to code taste quality. Fifteen participants sampled two concentrations of a pure sweet taste (sucrose), two sweet food odors (chocolate and strawberry), and two sweet floral odors (lilac and rose). Replicating prior work we found that olfactory stimulation activated the piriform, orbitofrontal and insular cortices. Of these regions, only the insula also responded to sweet taste. More importantly, the magnitude of the response to the food odors, but not to the non-food odors, in this region of insula was positively correlated with odor sweetness rating. These findings demonstrate that insular taste cortex contributes to odor quality coding by representing the taste-like aspects of food odors. Since the effect was specific to the food odors, and only food odors are experienced with taste, authors suggest this common central mechanism develops as a function of experiencing flavors.

(A) Coronal and sagittal sections of the area of insula where neural response to the food odors shows a positive correlation with the sweetness ratings of those odors. The main images display the unmasked regression maps while the insets labeled 1 depict the masked regressions (i.e., using the “sweet odors and sweet taste overlap” inclusive mask). The insets labeled 2 depict the analysis with the pleasantness and familiarity ratings as covariates. (B) Shows neural response (in parameter estimate) in the insula (at the maximally responding voxel at −45 −3 9), plotted against sweetness ratings for the food (red squares) and floral odors (yellow diamonds). (C) Illustrates the magnitude of the correlation (averaged across all voxels ± standard deviation) in the insula for food odors (in red squares) and non-food odor (yellow diamonds) in comparison to the responses in other areas for food and non-food odors vs. odorless. Note that although there appears to be a significant difference between food and floral odors in the left OFC, this effect this effect does not survive authors' criterion for significance in SPM and is therefore not discussed.

Reference: Veldhuizen MG, Nachtigal D, Teulings L, Gitelman DR and Small DM (2010) The insular taste cortex contributes to odor quality coding. Front. Hum. Neurosci. 4:58. doi: 10.3389/fnhum.2010.00058

Occipital cortex

Investigating representations of facial identity in human ventral visual cortex with transcranial magnetic stimulation
The occipital face area (OFA) is face-selective. This enhanced activation to faces could reflect either generic face and shape-related processing or high-level conceptual processing of identity. Here authors examined these two possibilities using a state-dependent transcranial magnetic stimulation (TMS) paradigm. The lateral occipital (LO) cortex which is activated non-selectively by various types of objects served as a control site. They localized OFA and LO on a per-participant basis using functional MRI. They then examined whether TMS applied to either of these regions affected the ability of participants to decide whether two successively presented and physically different face images were of the same famous person or different famous people. TMS was applied during the delay between first and second face presentations to investigate whether neuronal populations in these regions played a causal role in mediating the behavioral effects of identity repetition. Behaviorally they found a robust identity repetition effect, with shorter reaction times (RTs) when identity was repeated, regardless of the fact that the pictures were physically different. Surprisingly, TMS applied over LO (but not OFA) modulated overall RTs, compared to the No-TMS condition. But critically, authors found no effects of TMS to either area that were modulated by identity repetition. Thus, they found no evidence to suggest that OFA or LO contain neuronal representations selective for the identity of famous faces which play a causal role in identity processing. Instead, these brain regions may be involved in the processing of more generic features of their preferred stimulus categories. 

Stimuli examples and pixel-wise differences. (A) Examples of repeated identity trials stimuli (blue frame) and different identity trials stimuli (red frame). The first presented face image appears on the left, the second on the right. Repeated identity trials depicting Michelle Obama (top) and Tom Hanks (bottom). Different identity trials depicting Al Pacino, Dustin Hoffman, Britney Spears, and Scarlett Johansson are shown. See the list of individuals in Table 1; please note that these are examples for illustrative purposes and the exact images used in the experiment are available on request from the authors. (B) Pixel-wise differences for repeated identity trials and different identity trials (see further details in Materials and Methods). No significant difference in low-level image differences was found between the trial types. (C) Examples from the post hoc stimuli analysis: all stimuli were cropped to restrict the picture to the face only and normalized to a common size (see further details in Materials and Methods). (D) Pixel-wise differences as in (B) for the normalized images (described in C).

Reference: Gilaie-Dotan S, Silvanto J, Schwarzkopf DS and Rees G (2010) Investigating representations of facial identity in human ventral visual cortex with transcranial magnetic stimulation. Front. Hum. Neurosci.4:50. doi: 10.3389/fnhum.2010.00050  

Mapping psychiatric disorders

Mapping synaptic pathology within cerebral cortical circuits in subjects with schizophrenia
Converging lines of evidence indicate that schizophrenia is characterized by impairments of synaptic machinery within cerebral cortical circuits. Efforts to localize these alterations in brain tissue from subjects with schizophrenia have frequently been limited to the quantification of structures that are non-selectively identified (e.g., dendritic spines labeled in Golgi preparations, axon boutons labeled with synaptophysin), or to quantification of proteins using methods unable to resolve relevant cellular compartments. Multiple label fluorescence confocal microscopy represents a means to circumvent many of these limitations, by concurrently extracting information regarding the number, morphology, and relative protein content of synaptic structures. An important adaptation required for studies of human disease is coupling this approach to stereologic methods for systematic random sampling of relevant brain regions. In this review article authors consider the application of multiple label fluorescence confocal microscopy to the mapping of synaptic alterations in subjects with schizophrenia and describe the application of a novel, readily automated, iterative intensity/morphological segmentation algorithm for the extraction of information regarding synaptic structure number, size, and relative protein level from tissue sections obtained using unbiased stereological principles of sampling. In this context, authors provide examples of the examination of pre- and post-synaptic structures within excitatory and inhibitory circuits of the cerebral cortex.

(A). A schematic of a human brain, showing the superior temporal gyrus (STG) which can be sampled systematic uniformly random, shown here as a series of numbered blocks from which every other block (yellow) is selected for further processing. (B) Each of the selected blocks is further subsampled into a systematic random series of sections for microscopy [shown here for one of the blocks, with every other section in this example selected for further processing (yellow)]. (C) Within each sampled section the region of interest is identified (e.g., shown here as the yellow outline of deep layer 3 within the larger cytoarchitectonically defined Primary Auditory Cortex area of interest shown in dark gray). (D) An enlarged view of a portion of the region of interest showing a systematic random sampling grid which has been placed over each sampled section. Sites for microscopic sampling are identified by each grid intersection with the region of interest. (E) An enlarged view of a single sampling site, showing the optical disector located within the z-axis of the tissue section. The gray outlines represent the projections of the disector unto the superficial and deep surfaces of the tissue section. (F) A series of 2D confocal images at a fixed distance apart in the z-axis (see Other Technical Issues for a discussion of appropriate z-axis sampling distances) are collected at each sampling site. Immunoreactive synaptic structures are shown as red puncta. (G) The series of images are combined to form a 3D data set from each site, resulting in a sampled cube with x and y dimensions represented here in pixels and the z dimension as plane number. Within this data set, the disector can be conceived of as defined by a set of values in 3D. (H) Using the masking approach described above, a center of volume, that is a single point defined by x, y, z coordinates, can be assigned for each immunoreactive puncta. Puncta with centers of volume falling within the boundaries of the optical disector are sampled for quantification (shown here in green), while those puncta with centers of volume falling outside the disector, or touching one of the exclusion lines (red) are not selected for quantification. SF, Sylvian fissure; STS, superior temporal sulcus.

Reference:  Sweet RA, Fish KN and Lewis DA (2010) Mapping synaptic pathology within cerebral cortical circuits in subjects with schizophrenia. Front. Hum. Neurosci. 4:44. doi: 10.3389/fnhum.2010.00044


Hierarchical models of processing intelligible speech
There is now consensus that hierarchical processing is a key organizational aspect of the human cortical auditory system. Challenges for future studies include placing hierarchical organization in the temporal lobe within the broader context of larger networks for auditory and language processing, and clarifying the functional contribution of different parallel auditory processing pathways to comprehension of spoken language under varying degrees of effort.
(A) Hierarchical processing in the temporal lobe, showing a posterior-anterior gradient in acoustic insensitivity moving away from primary auditory cortex. Posterior and anterior regions of STS discussed by Okada et al. (2010) are outlined in white. (B) An expanded model of hierarchical processing for speech that includes prefrontal, premotor/motor, and posterior inferotemporal regions.

Reference: Peelle JE, Johnsrude IS and Davis MH (2010) Hierarchical processing for speech in human auditory cortex and beyond. Front. Hum. Neurosci. 4:51. doi: 10.3389/fnhum.2010.00051

Cognitive rehabilitation

Cognitive rehabilitation of episodic memory disorders: from theory to practice
Memory disorders are among the most frequent and most debilitating cognitive impairments following acquired brain damage. Cognitive remediation strategies attempt to restore lost memory capacity, provide compensatory techniques or teach the use of external memory aids. Memory rehabilitation has strongly been influenced by memory theory, and the interaction between both has stimulated the development of techniques such as spaced retrieval, vanishing cues or errorless learning. These techniques partly rely on implicit memory and therefore enable even patients with dense amnesia to acquire new information. However, knowledge acquired in this way is often strongly domain-specific and inflexible. In addition, individual patients with amnesia respond differently to distinct interventions. The factors underlying these differences have not yet been identified. Behavioral management of memory failures therefore often relies on a careful description of environmental factors and measurement of associated behavioral disorders such as unawareness of memory failures. The current evidence suggests that patients with less severe disorders benefit from self-management techniques and mnemonics whereas rehabilitation of severely amnesic patients should focus on behavior management, the transmission of domain-specific knowledge through implicit memory processes and the compensation for memory deficits with memory aids. 

Learning capacity, spatio-temporal orientation, awareness of the deficit, and independence in activities of daily living (ADL) as a function of the degree of memory impairment (click on the table to enlarge).

Reference: Ptak R, Van der Linden M and Schnider A (2010) Cognitive rehabilitation of episodic memory disorders: from theory to practice. Front. Hum. Neurosci. 4:57. doi: 10.3389/fnhum.2010.00057

Frontal cortex

Virtual reality and the role of the prefrontal cortex in adults and children
In this review the neural underpinnings of the experience of presence are outlined. Firstly, it is shown that presence is associated with activation of a distributed network, which includes the dorsal and ventral visual stream, the parietal cortex, the premotor cortex, mesial temporal areas, the brainstem and the thalamus. Secondly, the dorsolateral prefrontal cortex (DLPFC) is identified as a key node of the network as it modulates the activity of the network and the associated experience of presence. Thirdly, children lack the strong modulatory influence of the DLPFC on the network due to their unmatured frontal cortex. Fourthly, it is shown that presence-related measures are influenced by manipulating the activation in the DLPFC using transcranial direct current stimulation (tDCS) while participants are exposed to the virtual roller coaster ride. Finally, the findings are discussed in the context of current models explaining the experience of presence, the rubber hand illusion, and out-of-body experiences.
Demonstration of brain areas that are more strongly activated during the presentation of a roller coaster scenario that evokes high presence versus low presence. (A) Increased hemodynamic responses overlaid on a three-dimensional (3D) rendered brain and two sagittal brain slices. (B) Schematic depiction of the stronger activated brain areas during the high presence condition
Reference: Jäncke L, Cheetham M and Baumgartner T (2009). Virtual reality and the role of the prefrontal cortex in adults and children. Front. Neurosci . 3,1: 52–59. doi: 10.3389/neuro.01.006.20009  Full text