Anatomical MRI of the developing human brain: what have we learned?

OBJECTIVE: To critically review and integrate the existing literature on magnetic resonance imaging (MRI) studies of the normally developing brain in childhood and adolescence and discuss the implications for clinical MRI studies. METHOD: Changes in regional brain volume with age and differences between the sexes are summarized from reports in refereed journal articles pertaining to MRI of the developing human brain. RESULTS: White matter volume increases with age. Gray matter volumes increase during childhood and then decrease before adulthood. On average, boys have larger brains than girls; after correction for overall brain volume the caudate is relatively larger in girls, and the amygdala is relatively larger in boys. Differences are of clinical interest given gender-related differences in the age of onset, symptomatology, and prevalence noted for nearly all childhood-onset psychiatric disorders. Attention-deficit/hyperactivity disorder is frequently used as an example to demonstrate these points. CONCLUSIONS: Understanding the developmental trajectories of normal brain development and differences between the sexes is important for the interpretation of clinical imaging studies.     

Functional and structural brain networks in epilepsy: What have we learned?

Brain functioning is increasingly seen as a complex interplay of dynamic neural systems that rely on the integrity of structural and functional networks. Recent studies that have investigated functional and structural networks in epilepsy have revealed specific disruptions in connectivity and network topology and, consequently, have led to a shift from “focus” to “networks” in modern epilepsy research. Disruptions in these networks may be associated with cognitive and behavioral impairments often seen in patients with chronic epilepsy. In this review, we aim to provide an overview that would introduce the clinical neurologist and epileptologist to this new theoretical paradigm. We focus on the application of a theory, called “network analysis,” to characterize resting‐state functional and structural networks and discuss current and future clinical applications of network analysis in patients with epilepsy.     

Nose and headache: what have we learned?

Sinonasal involvement in secondary headache has long been interpreted as sinusitis and overestimation has been a problem in the past. In the last 20 years, the innovative interpretation of contact points between the lateral nasal wall and the septum as triggering cause of facial pain via the trigeminovascular system has gained importance in nasal secondary headaches. Also in this case, the prevalence and relevance has been misinterpreted in the beginning, undermining the success rate of pain improvement after surgical removal of these contact points. Therefore, studies have started to concentrate on the need of suitable preoperative evaluation to define the ideal, responsive candidate for surgical management of this form of headache. This article analyzes the outcome of these studies and tries to highlight the need for long-term follow-up to finally determine the relevance of surgical treatment for this particular headache form.

     

Prisms and neglect: What have we learned?

Since Rossetti et al. (1998) reported that prism adaptation (PA) can lead to a substantial reduction of neglect symptoms PA has become a hot topic in neglect-research. More than 280 articles have been published in this area. Not all of those studies investigated the therapeutic potential of this technique, many studies examined the responsiveness to PA as a way to subdivide neglect into separate subsyndromes, other studies focussed on the process of PA itself in an effort to illuminate its underlying neurobiological mechanisms. In this article we will review research in all of these three areas to determine whether and to what extent research on PA in neglect patients has fulfilled its promise as a new way to improve the treatment of neglect, enhance our understanding of this complex syndrome and provide new insights into the neurobiology of sensorimotor learning.     

STEP-BD and bipolar depression: What have we learned?

This article summarizes recent findings from the STEP-BD project pertaining to bipolar depression treatment. Highlighted are four papers that report, in turn, a large, randomized controlled trial of adjunctive antidepressants; a large, randomized controlled trial of adjunctive psychosocial therapies (cognitive-behavioral therapy, interpersonal social rhythms therapy, and family-focused therapy); a small, randomized controlled trial contrasting lamotrigine, risperidone, and inositol as add-on therapies for refractory bipolar depression; and a naturalistic study of the risks of relapse during preventive therapy. The STEP-BD results highlight the challenge of treating bipolar depression to remission, illustrate the value of adjunctive psychotherapies, and point to new directions for research.     

Stroke trials: what have we learned?

We reviewed the recent, major, therapeutic trials of intravenous thrombolytic therapy and ancrod for ischemic stroke. Randomized, controlled studies of acute ischemic stroke treatment were reviewed. Several post-FDA approval intravenous tPA studies were reviewed to understand the experience of this medication in practice. STAT trial was the major study using ancrod. Of multiple intravenous thrombolytic studies, the NINDS study of intravenous tPA was the only study to demonstrate a significantly higher percentage of patients with complete recovery or minimal deficit at three months. Studies in communities utilizing intravenous tPA for stroke illustrate the need for close adherence to the NINDS study protocol or else the risk of tPA use may exceed the benefits.     

Magnetic resonance spectroscopy and schizophrenia: what have we learnt?

OBJECTIVE: Magnetic resonance spectroscopy (MRS) has been increasingly used to investigate the in vivo biochemistry of particular regions of the brain in patients with schizophrenia. We review the literature and discuss the theoretical constructs that form the presumed impetus for these studies in light of the current methodological limitations. Future directions are noted. METHOD: The available published literature in English formed the basis for this review. RESULTS: The results of 31P-MRS have been interpreted as reflecting a relative increase in cell membrane degradation in prefrontal cortical regions at certain phases of schizophrenia. 1H-MRS studies, though less consistent, provide evidence suggestive of a decrease in neuronal cell mass in the hippocampal region, which supports the findings of volumetric studies. Both groups of MRS studies support a neuro-developmental hypothesis of brain dysfunction in schizophrenia. However, current methodological problems limit the reliable interpretation of MRS data. A clear understanding of the methodology and its reliable interpretation is yet to emerge. CONCLUSIONS: MRS remains a research instrument that is yet to be fully utilised in schizophrenia research. A few replicated findings are emerging, although the interpretation of these spectroscopic findings needs to be validated.     

Molecular genetics of Alzheimer's disease: what have we learned?

Alzheimer's disease (AD), by far the most common form of dementia in the elderly, is clinically characterized by gradual, progressive loss in cognitive functioning and changes in personality, ultimately leading to death. It is now well established that genetic factors play an important role in AD. So far, three genes have been identified in which mutations cause autosomal-dominant AD: the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and the homologous presenilin 2 (PSEN2) gene on chromosome 1. A major susceptibility gene, the apolipoprotein E (APOE) gene, was identified on chromosome 19.     

Jargon aphasia: What have we learned?

Background: Jargon aphasia is one of the most puzzling and clinically intractable forms of aphasia. It challenges us to think not only about the loss of normal language but also about the apparent acquisition of a strange and novel form of production.

Aims: This paper aims to review the literature about jargon aphasia in order to provide an overview of our current knowledge of the condition.

Main Contribution: The paper will cover five themes: nonword production, monitoring in jargon aphasia, writing in jargon aphasia, semantic jargon, and syntax in jargon aphasia. It attempts to review and appraise some of the key explanations for the phenomena of jargon.

Conclusions: It is acknowledged that many of the questions posed by jargon aphasia remain unresolved. Nevertheless, some tentative explanations for the production of jargon are proposed.     

Animal models of the ketogenic diet: what have we learned, what can we learn?

Despite its clinical use as a therapy for refractory epilepsy for more than 75 years, the ketogenic diet (KD) remains a therapy in search of an explanation. The mechanism of action of the KD is unclear and the optimal indications for its clinical use are incompletely defined. Animal models could help to elucidate these questions. Surprisingly, there have been very few animal studies of the KD, and those that have been performed are difficult to compare because of wide discrepancies in experimental methods. Earlier models concentrated on the effect of the KD on acute seizure threshold in normal (i.e. nonepileptic) animals. Recent studies are beginning to examine the longer term effects of the KD and its role in epileptogenesis. Some features of clinical experience have been replicated in animal models, including the role of ketosis, elevation of seizure threshold by both classic ketogenic and medium chain triglyceride diets, better effectiveness at younger ages, and rapid reversal of the seizure protective effect when the diet is discontinued. These parallels raise hope that pertinent clinical questions can be addressed in the more controlled setting of the research laboratory. As in the clinical arena, there has been a recent resurgence of interest in pursuing basic questions related to the ketogenic diet, using techniques of modern neuroscience. Experimental approaches such as brain slice neurophysiology, genetic models, dissection of metabolic pathways, and neurohistological techniques hold much promise in the effort to understand this intriguing alternative to standard anticonvulsants.     

Cognitive treatments of sentence processing disorders: What have we learned?

Several cognitive neuropsychological studies describing treatments of sentence processing disorders have been reported in recent years. We review the outcome of 10 studies that describe treatment outcomes for 17 aphasic patients. Although the studies used different approaches to intervention, they shared the goal of improving reversible sentence comprehension, and they targeted a hypothesised deficit of “thematic mapping”. Several trends in treatment outcomes were observed. In most cases, there was strong evidence that the treatments induced a change in the pattern of sentence processing. Moreover, the outcomes indicated that impaired reversible sentence comprehension can arise from a range of impairments, only some of which directly implicate structural and/or lexical deficits assumed to be the source of poor thematic mapping abilities. Patterns of post-therapy generalisation within and across processing modalities appeared to be related, among other things, to the therapy approach and to the selection of treatment materials. These findings are discussed with regard to the theoretical implications of sentence processing treatment data.     

Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far?

Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side-effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C-reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets.     

Neuroimaging in bipolar disorder: what have we learned?

New technologies are offering increasingly powerful means to obtain structural, chemical, and functional images of the brain during life, often without the use of ionizing radiation. Bipolar disorder, with its clear physiologic features, would appear to be a prime candidate for the application of current brain imaging; however, only a modest number of studies have been reported to date, and most studies have small sample sizes and heterogeneous subject groups. Nonetheless, there are a few consistent findings among these studies, including the following: 1) Structural imaging studies suggest an increased number of white matter hyperintensities in patients with bipolar disorder. These may be lesions unique to bipolar disorder and its treatment, or related to cardiovascular risk factors, which are more common in bipolar patients. Decreased cerebellar size and anomalies of cerebellar blood volume have also been reported. Increased sulcal prominence and enlargement of the lateral and third ventricles are less consistently observed findings. 2) Spectroscopic imaging suggests abnormalities of metabolism of choline-containing compounds in symptomatically ill bipolar patients and, possibly, treatment-induced changes in choline- and myoinositol-containing compounds. Each of these groups of metabolites serves as a component of membrane phospholipids and cellular second-messenger cycles. 3) Metabolic and blood flow studies provide evidence for decreased activity of the prefrontal cortex (PFC) in bipolar patients during depression. It is not clear if these changes are restricted to particular subregions of the PFC, nor if they are reversed with mania. No single pathophysiologic mechanism yet explains these findings, although all might be due to regional alterations in cellular activity and metabolism or changes in cell membrane composition and turnover. The development of imaging technologies has far outpaced their use in bipolar disorder. The promise of future studies is great, with more powerful magnetic resonance scanners, additional ligands for positron emission tomography and single photon emission computed tomography imaging, and improved image generation and processing already available.