Getting neurorehabilitation right: what can be learned from animal models?

Animal models suggest that a month of heightened plasticity occurs in the brain after stroke, accompanied by most of the recovery from impairment. This period of peri-infarct and remote plasticity is associated with changes in excitatory/inhibitory balance and the spatial extent and activation of cortical maps and structural remodeling. The best time for experience and training to improve outcome is unclear. In animal models, very early (<5 days from onset) and intense training may lead to increased histological damage. Conversely, late rehabilitation (>30 days) is much less effective both in terms of outcome and morphological changes associated with plasticity. In clinical practice, rehabilitation after disabling stroke involves a relatively brief period of inpatient therapy that does not come close to matching intensity levels investigated in animal models and includes the training of compensatory strategies that have minimal impact on impairment. Current rehabilitation treatments have a disappointingly modest effect on impairment early or late after stroke. Translation from animal models will require the following: (1) substantial increases in the intensity and dosage of treatments offered in the first month after stroke with an emphasis on impairment; (2) combinational approaches such as noninvasive brain stimulation with robotics, based on current understanding of motor learning and brain plasticity; and (3) research that emphasizes mechanistic phase II studies over premature phase III clinical trials.     

Cognitive dysfunction and depression in Parkinson's disease: what can be learned from rodent models?

Parkinson's disease (PD) has for decades been considered a pure motor disorder and its cardinal motor symptoms have been attributed to the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and to nigral Lewy body pathology. However, there has more recently been a shift in the conceptualization of the disease, and its pathological features have now been recognized as involving several other areas of the brain and indeed even outside the central nervous system. There are a corresponding variety of intrinsic non-motor symptoms such as autonomic dysfunction, cognitive impairment, sleep disturbances and neuropsychiatric problems, which cannot be explained exclusively by nigral pathology. In this review, we will focus on cognitive impairment and affective symptoms in PD, and we will consider whether, and how, these deficits can best be modelled in rodent models of the disorder. As only a few of the non-motor symptoms respond to standard DA replacement therapies, the quest for a broader therapeutic approach remains a major research effort, and success in this area in particular will be strongly dependent on appropriate rodent models. In addition, better understanding of the different models, as well as the advantages and disadvantages of the available behavioural tasks, will result in better tools for evaluating new treatment strategies for PD patients suffering from these neuropsychological symptoms.     

What can be learned from the effects of benzodiazepines on exploratory behavior?

The purpose of this review is to assess the value of using tests of exploratory behavior to study the actions of benzodiazepines. The methods of measuring exploration and the factors influencing it are briefly described. The effects of benzodiazepines on exploratory behavior of rats and mice are reviewed; and the dangers of interpreting the results of such tests in terms of any of the clinical effects of the benzodiazepines is stressed. Finally, the interactions between benzodiazepines and other drugs acting at the GABA-benzodiazepine receptor complex are described. The results of these experiments caution against global classification of compounds as benzodiazepine "antagonists."     

Ocular manifestation of primary nervous system lymphoma: what can be expected from imaging?

Primary ocular lymphoma, which affects the posterior parts of the eye, is an ocular manifestation of primary central nervous system lymphoma (PCNSL). It used to be the ocular disease with the shortest time of survival, even worse than ocular melanoma. Death ensues by CNS dissemination. Unfortunately, ocular lymphoma may be the initial manifestation of PCNSL and diagnosis is frequently difficult, even if vitreal biopsy is performed. Therefore, it should be determined whether cross sectional imaging may be helpful in detection and differential diagnosis of ocular lymphoma. MRI of seven patients (female = 6, male = 1, median age 62 years) with biopsy proven ocular lymphoma were retrieved from the files of our hospital and of a multicenter PCNSL study. In four patients, ocular lymphoma was the first manifestation of PCNSL, in three a cerebral lesion had occurred in the first place. Progression to cerebral lymphoma was seen in three of the four patients with initial eye manifestation. Imaging was performed using a dedicated thin section protocol in four patients. An intraocular abnormality was found in four cases, always in T1-weighted images after contrast injection. Differential diagnosis from uveitis or ocular melanoma was not possible by imaging alone. The examination was falsely negative in the remaining three patients. Hence, imaging has a low sensitivity for ocular lymphoma and does not facilitate differential diagnosis against uveitis or ocular melanoma. Received: 17 April 2002, Accepted: 9 July 2002 Correspondence to Dr. W. Küker     

A risk profile of the aggressive psychiatric inpatient: can it be identified?

Violent behavior of psychiatric inpatients has grown in interest. Within the scope of a prospective study,patient assaults in six psychiatric hospitals of the Swiss Canton of Zurich were assessed during a period of 6 months, from November 1999 until May 2000. Three hundred eighty-eight of 5,251 inpatients (7.4%) were reported to act aggressively. The following risk factors for aggressive behavior were identified: male gender, younger age, unemployment, severity of mental illness, and rehospitalization. Psychiatric diagnosis was not related to aggressiveness. In spite of the detection of risk factors, a characteristic profile of aggressive psychiatric inpatients cannot be stated. Research should pay more attention to situation-specific cues for the aggressive behavior of such individuals.     

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.     

Relapse in medulloblastoma: what can be done after abandoning high-dose chemotherapy? A mono-institutional experience

Purpose

We retrospectively report strategies used for medulloblastoma patients progressing after craniospinal irradiation where we aimed for: symptom control, a satisfactory quality of life, accrual in phase 1–2 trials, when available, and the first two conditions could no longer be satisfied by already experienced second-line strategies.

Methods

Surgery was used in cases of doubtful relapse or when only one site was affected. Radiotherapy was given whenever possible, especially to relieve symptoms. The main chemotherapy regimens were oral temozolomide/etoposide, intravenous (iv.) cisplatin/etoposide, iv. gemcitabine/oxaliplatin, an oral sonic hedgehog pathway inhibitor and oral melphalan.

Results

Between 1998 and 2011, we treated 18 patients relapsed after median 20 months. Nine had relapsed locally, four had dissemination, three single metastases, and two had one synchronous local and metastatic recurrence. Responses to chemotherapy were seen in 32 % of cases. The median hospital stay for treatments/complications was 19 days. The 1- and 3-year progression-free survival (PFS) rates were 28?±?10 % and 0 %, respectively, for OS, they were 44?±?12 % and 22?±?10 % but no patient was cured. The median PFS after a first relapse was 7 months (range 1–29); the median OS was 7 months (range 4–44). No patients died due to treatment toxicity. Late recurrence (more than 1–2 years after diagnosis) and involvement of single sites were favorable prognostic factors.

Conclusions

Without succeeding in patients cure, we ensured them further treatment with short hospital stay thus affording low personal and social costs. The chances of cure may emerge from tailored therapies according to genetic stratification.     

A follow-up study of adolescents with conduct disorder: can long-term outcome be predicted from psychiatric assessment data?

This study examines Swedish young adults (mean age 21) with a history of conduct disorder (CD) as adolescents. Using medical records, this study explores the relationship between adolescent inpatients and their outcomes in adulthood. Two outcome variables were used: an indication of non-successful outcome variable (seven undesirable outcomes) and sense of coherence. Using multiple regression analyses, this study showed that extracted data from the medical case record could significantly explain small variance depending on output variable. The small variance could be related to the homogeneous clinical sample, the follow-up time, the outcome variables and the absence of a biological perspective. This study suggest, clinicians should be very careful when predicting outcome in young adulthood, if they should predict outcome at all. The positive conclusion in this matter is that as far as we know any teenager with CD could have a positive outcome in young adulthood.     

An exploration of research into substance misuse and psychiatric disorder in the UK: what can we learn from history?

BACKGROUND AND AIM: This review explores UK-based research developments in substance misuse and mental illness over the last 25 years. The main body of work comprises policy-orientated projects funded by the Department of Health from the late 1990s. Early research tended to focus on alcohol, especially alcoholic hallucinosis: the relationship of the latter with schizophrenia-like illness was examined, with the finding that very few cases did develop into schizophrenia. METHOD AND IMPLICATIONS: Parallels are drawn with the current debate around the link between cannabis and psychosis, urging caution in too rapid an assertion that cannabis is necessarily 'causal'. The clinical and policy implications of the misinterpretation of evidence are discussed. A proposal is put forward that the genesis of psychotic illness in alcohol misuse be revisited using more sophisticated research methodologies. Given the changing landscape of substance use in the UK, particularly the fashion of polysubstance use and the recognition that this is associated with psychotic illness, other drugs that are associated with psychotic illness should be similarly investigated to determine whether there is a common mechanism that might throw light on understanding the relationship between substance use and psychotic illness or schizophrenia.     

Commentary: psychiatric advance directives at a crossroads--when can PADs be overridden?

Current statutes enabling psychiatric advance directives (PADs) typically include provisions allowing override of patients' choices by treatment staff. Lest the purpose of the PAD be vitiated by too broad an application of the override mechanism, its use should be carefully limited. In inpatient settings, voluntary patients should have the right to decline treatments in advance, although not an absolute right to demand treatments of their choosing. The situation of involuntary patients is more complex. Permitting PADs to trump commitment statutes would undercut the combined parens patriae/police power rationale for commitment, a path taken currently by no U.S. jurisdiction. Moreover, PADs should not be permitted to negate the usual mechanisms for involuntary treatment of committed patients; to do otherwise risks forcing facilities to confine indefinitely persons they cannot treat. Even in those circumstances, however, where PADs provide evidence of reasonable patient preferences (e.g., for one medication over another), the choices they embody should be respected.     

Delirium phenomenology: what can we learn from the symptoms of delirium?

OBJECTIVES: This review focuses on phenomenological studies of delirium, including subsyndromal and prodromal concepts, and their relevance to other elements of clinical profile. METHODS: A Medline search using the keywords delirium, phenomenology, and symptoms for new data articles published in English between 1998 and 2008 was utilized. The search was supplemented by additional material not identified by Medline but known to the authors. RESULTS: Understanding of prodromal and subsyndromal concepts is still in its infancy. The characteristic profile can differentiate delirium from other neuropsychiatric disorders. Clinical (motoric) subtyping holds potential but more consistent methods are needed. Studies are almost entirely cross-sectional in design and generally lack comprehensive symptom assessment. Multiple assessment tools are available but are oriented towards hyperactive features and few have demonstrated ability to distinguish delirium from dementia. There is insufficient evidence linking specific phenomenology with etiology, pathophysiology, management, course, and outcome. CONCLUSIONS: Despite the major advancements of the past decade in many aspects of delirium research, further phenomenological work is crucial to targeting studies of causation, pathophysiology, treatment, and prognosis. We identified eight key areas for future studies.     

Cytokines as mediators of depression: what can we learn from animal studies?

It has recently been postulated that cytokines may cause depressive illness in man. This hypothesis is based on the following observations: 1. Treatment of patients with cytokines can produce symptoms of depression; 2. Activation of the immune system is observed in many depressed patients; 3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction; 4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with antidepressants has been shown to inhibit sickness behavior induced by LPS; 5. Several cytokines can activate the hypothalamo-pituitary-adrenocortical axis (HPAA), which is commonly activated in depressed patients; 6. Some cytokines activates cerebral noradrenergic systems, also commonly observed in depressed patients; 7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment. The evidence for each of these tenets is reviewed and evaluated along with the effects of cytokines in classical animal tests of depression. Although certain sickness behaviors resemble the symptoms of depression, they are not identical and each has distinct features. Thus the value of sickness behavior as an animal model of major depressive disorder is limited, so that care should be taken in extrapolating results from the model to the human disorder. Nevertheless, the model may provide insight into the etiology and the mechanisms underlying some symptoms of major depressive disorder. It is concluded that immune activation and cytokines may be involved in depressive symptoms in some patients. However, cytokines do not appear to be essential mediators of depressive illness.     

Maintenance treatment of insomnia: what can we learn from the depression literature?

Insomnia and depression are common problems with profound public health consequences. When left untreated, both conditions have high rates of persistence and recurrence. Maintenance treatment for depression is fairly well established, but there is no evidence-based consensus regarding the safety and efficacy of maintenance therapy for insomnia. Consequently, long-term treatment of insomnia is driven primarily by the individual choices of patients and their clinicians. This article compares and contrasts the current state of research in the maintenance therapy of depression and insomnia and highlights gaps in the insomnia literature.     

Treatment adherence: what is the best that can be achieved?

The modest effectiveness of disease modifying therapies (DMTs) in MS has been amply illustrated by a series of pivotal trials, albeit short term in the context of a life-long disease. Most neurologists and people with MS welcome the opportunity to affect the course of this disorder. However, the individual with MS might not be fully aware of the importance of continuing treatment with these drugs in the absence of feeling better (and often feeling worse) while taking therapy.     

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.     

The role of parietal cortex in visuomotor control: what have we learned from neuroimaging?

Research from macaque neurophysiology and human neuropsychology has implicated the parietal cortex in the sensory control of action. Functional neuroimaging has been very valuable in localizing and characterizing specific regions of the human brain involved in visuomotor actions involving different effectors, such as the eyes, head, arms and hands. Here, we review the areas discovered by human neuroimaging, including the putative functional equivalents of the following macaque regions: parietal eye fields (PEF), ventral intraparietal (VIP) area, parietal reach region (PRR) and the anterior intraparietal (AIP) area. We discuss the challenges of studying realistic movements in the imaging environment, the lateralization of visuomotor function, caveats involved in proposing interspecies homologies and the limitations and future directions for neuroimaging studies of visuomotor control.     

An open hypothesis: is epilepsy learned, and can it be unlearned?

Plasticity is central to the ability of a neural system to learn and also to its ability to develop spontaneous seizures. What is the connection between the two? Learning itself is known to be a destabilizing process at the algorithmic level. We have investigated necessary constraints on a spontaneously active Hebbian learning system and find that the ability to learn appears to confer an intrinsic vulnerability to epileptogenesis on that system. We hypothesize that epilepsy arises as an abnormal learned response of such a system to certain repeated provocations. This response is a network-level effect. If epilepsy really is a learned response, then it should be possible to reverse it, that is, to unlearn epilepsy. Unlearning epilepsy may then provide a new approach to its treatment.