Brain imaging research: does the science serve clinical practice?

Brain imaging represents a potent tool to characterize biomarkers, biological traits that are pathognomonic for specific neurological and neuropsychiatric disorders. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are imaging techniques used to identify alterations in the density and distribution of neurotransmitters, neuroreceptors, and transporters in specific regions of the brains of people with these disorders. Brain imaging research currently facilitates the elucidation of dysfunction of dopamine, serotonin, acetylcholine, and other substances in people with Alzheimer's and Parkinson's diseases, schizophrenia, alcoholism and other substance abuse disorders, attention deficit/hyperactivity disorder, and the syndromes of restless legs, Lesch-Nyhan, Rett, and Tourette. Thus, brain imaging research offers great potential for the diagnosis, treatment, prevention, and cure of neurological and neuropsychiatric disorders. Brain imaging research also facilitates new drug development and helps establish therapeutic doses of novel drugs. In particular, studies of specific receptors, such as the dopamine D2 receptor, before and after the administration of doses of drugs that occupy these D2 receptors, provide the means to determine receptor occupancy. For example, an optimal dose of D2 antagonist antipsychotics produces occupancy of 65% to 80% of D2 receptors, while a greater dose carries a risk of extrapyramidal side effects.     

Brain imaging research: Does the science serve clinical practice?

Brain imaging represents a potent tool to characterize biomarkers, biological traits that are pathognomonic for specific neurological and neuropsychiatric disorders. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are imaging techniques used to identify alterations in the density and distribution of neurotransmitters, neuroreceptors, and transporters in specific regions of the brains of people with these disorders. Brain imaging research currently facilitates the elucidation of dysfunction of dopamine, serotonin, acetylcholine, and other substances in people with Alzheimer's and Parkinson's diseases, schizophrenia, alcoholism and other substance abuse disorders, attention deficit/hyperactivity disorder, and the syndromes of restless legs, Lesch-Nyhan, Rett, and Tourette. Thus, brain imaging research offers great potential for the diagnosis, treatment, prevention, and cure of neurological and neuropsychiatric disorders. Brain imaging research also facilitates new drug development and helps establish therapeutic doses of novel drugs. In particular, studies of specific receptors, such as the dopamine D₂ receptor, before and after the administration of doses of drugs that occupy these D₂ receptors, provide the means to determine receptor occupancy. For example, an optimal dose of D₂ antagonist antipsychotics produces occupancy of 65% to 80% of D₂ receptors, while a greater dose carries a risk of extrapyramidal side effects.     

How should functional imaging of patients with disorders of consciousness contribute to their clinical rehabilitation needs?

PURPOSE OF REVIEW: We discuss the problems of evidence-based neurorehabilitation in disorders of consciousness, and recent functional neuroimaging data obtained in the vegetative state and minimally conscious state. RECENT FINDINGS: Published data are insufficient to make recommendations for or against any of the neurorehabilitative treatments in vegetative state and minimally conscious state patients. Electrophysiological and functional imaging studies have been shown to be useful in measuring residual brain function in noncommunicative brain-damaged patients. Despite the fact that such studies could in principle allow an objective quantification of the putative cerebral effect of rehabilitative treatment in the vegetative state and minimally conscious state, they have so far not been used in this context. SUMMARY: Without controlled studies and careful patient selection criteria it will not be possible to evaluate the potential of therapeutic interventions in disorders of consciousness. There also is a need to elucidate the neurophysiological effects of such treatments. Integration of multimodal neuroimaging techniques should eventually improve our ability to disentangle differences in outcome on the basis of underlying mechanisms and better guide our therapeutic options in the challenging patient populations encountered following severe acute brain damage.     

Editorial: Can neuroscience add to clinical practice?

Neuroscience is advancing rapidly, but has so far generated few applications for clinicians in mental health. Nevertheless, it is time to consider how clinical practice might evolve to use an improving technology for individual patients, and this Editorial explores this by looking at how neuroimaging may lead to objective diagnosis, help in analysing dysfunctions and discovering new treatments and guiding more established ones for child and adolescent mental health disorders.     

Is it time to introduce repetitive transcranial magnetic stimulation into standard clinical practice for the treatment of depressive disorders?

OBJECTIVE: To examine issues relating to the potential introduction of repetitive transcranial magnetic stimulation (rTMS) into clinical practice as a treatment for depression. METHOD: A review of the outcomes literature accompanied by an analysis of issues relating to the potential advantages and pitfalls of the introduction of rTMS as a treatment strategy. RESULTS: Evidence is progressively accumulating that rTMS has antidepressant properties that are clinically relevant. These effects are biologically plausible and supported by basic research. Patients with therapy-resistant depression have few treatment alternatives and experience significant suffering, thus justifying the early introduction of a new treatment such as rTMS for this patient group. However, this must be balanced by a need to foster considerable further research and not to raise expectations unreasonably. CONCLUSIONS: It is timely for rTMS to be made more available to patients with treatment-resistant mood disorders. This need not be limited to clinical research trials but should only occur in medical settings where continual evaluation and research is conducted.     

Dystonia and the cerebellum: A new field of interest in movement disorders?

Although dystonia has traditionally been regarded as a basal ganglia dysfunction, recent provocative evidence has emerged of cerebellar involvement in the pathophysiology of this enigmatic disease. This review synthesizes the data suggesting that the cerebellum plays an important role in dystonia etiology, from neuroanatomical research of complex networks showing that the cerebellum is connected to a wide range of other central nervous system structures involved in movement control to animal models indicating that signs of dystonia are due to cerebellum dysfunction and completely disappear after cerebellectomy, and finally to clinical observations in secondary dystonia patients with various types of cerebellar lesions. We propose that dystonia is a large-scale dysfunction, involving not only cortico-basal ganglia-thalamo-cortical pathways, but the cortico-ponto-cerebello-thalamo-cortical loop as well. Even in the absence of traditional “cerebellar signs” in most dystonia patients, there are more subtle indications of cerebellar dysfunction. It is clear that as long as the cerebellum’s role in dystonia genesis remains unexamined, it will be difficult to significantly improve the current standards of dystonia treatment or to provide curative treatment.     

Prospective studies of cothymia (mixed anxiety-depression): how do they inform clinical practice?

We suggest that the diagnosis of mixed anxiety depression at syndromal level (i.e. both anxiety and depressive diagnoses present in the same person and given equal status) is valuable clinically and should be introduced into the formal classification of neurotic and mood disorders. Evidence is given from a systematic review that cothymia has a significantly worse outcome than either an anxiety or a depressive diagnosis alone (p < 0.0001). Long-term follow-up data in a 12-year outcome study of neurotic disorder reinforce this finding both with regard to social functioning and the clinical course of anxiety and depressive disorders; these were significantly worse (P < 0.001 and P < 0.02 respectively) in those with cothymia compared with single anxiety disorders. These outcome differences are much greater than those between anxiety and depressive disorders alone.     

Neuroimaging of attention deficit hyperactivity disorder: can new imaging findings be integrated in clinical practice?

Recent advances in neuroimaging research have helped elucidate the neurobiology of attention deficit hyperactivity disorder (ADHD) and the mechanisms by which medications used to treat ADHD exert their effects. The complex nature and array of imaging techniques, however, present challenges for the busy clinician in assessing possible clinical uses of brain imaging. Even though currently there are no accepted uses for imaging in diagnosing ADHD (other than ruling out identifiable medical or neurologic conditions that may mimic ADHD), this review introduces the main imaging techniques used to study ADHD, identifies relevant complexities facing psychiatric researchers in implementing neuroimaging techniques for clinical purposes, and provides benchmarks to help determine when imaging modalities have advanced to a point that they are deemed clinically useful.     

Pregnancy registries: What do they mean to clinical practice?

Multiple surveillance pregnancy registries have been established in order to better understand the effects of antiepileptic drugs (AEDs) on pregnancy. These registries are either hospital based, population based, or pharmaceutical based and are primarily focused on the potential teratogenicity of AEDs. The main outcome variable for most of these registries is the risk of major congenital malformations. Registries also gather data on other aspects of pregnancy, including seizure control. The methodology of the registries varies. They have different populations, ascertainment strategies, follow-up, and reporting criteria. These differences limit the ability to allow direct comparisons. Overall, the registry data suggest that the overwhelming majority of women with epilepsy treated with AEDs will have normal, healthy babies. A second consistent finding is that valproate, particularly at higher doses, is associated with a higher risk of major congenital malformations than other AEDs.     

Brain imaging technologies: how, what, when and why?

OBJECTIVE: Innovations in physics and computing technology over the past two decades have provided a powerful means of exploring the overall structure and function of the brain using a range of computerised brain imaging technologies (BITs). These technologies offer the means to elucidate the patterns of pathophysiology underlying mental illness. The aim of this paper is to explore the current status and some of the future directions in the application of BITs to psychiatry. METHOD: Brain imaging technologies provide unambiguous measures of brain structure (computerised tomography and magnetic resonance imaging [MRI]) and also index complementary measures of when (electroencephalography, event related potentials, magnetoencephalography) and where (functional MRI, single photon emission computed tomography, positron emission tomography) aspects of brain activity occur. RESULTS: The structural technologies are primarily used to exclude a biological cause in cases of a suspected psychiatric disorder. The functional technologies show considerable potential to delineate subgroups of patients (that may have different treatment outcomes), and evaluate objectively the effects of treatment on the brain as a system. What is seldom emphasised in the literature are the numerous inconsistencies, the lack of specificity of findings and the simplistic interpretation of much of the data. CONCLUSION: Brain imaging technologies show considerable utility, but we are barely scratching the surface of this potential. Simplistic over-interpretation of results can be minimised by: replication of BIT findings, judicious combination of complementary methodologies, use of appropriate activation tasks, analysis with respect to large normative databases, control for performance, examining the data'beyond averaging', delineating clinical subtypes, exploring the severity of symptoms, specificity of findings and effects of treatment in the same patients. The technological innovation of BITs still far outstrips the sophistication of their use; it is essential that the meaning and mechanisms underlying BIT measures are always evaluated with respect to prevailing models of brain function across disciplines.     

Integration of the sensory inputs to place cells: what, where, why, and how?

The hippocampal place cells are a highly multimodal class of neurons, receiving information from many different sensory sources to correctly localize their firing to restricted regions of an environment. Evidence suggests that the sensory information is processed upstream of the hippocampus, to extract both angular and linear metric information, and also contextual information. These various kinds of information need to be integrated for coherent firing fields to be generated, and the present article reviews recent evidence concerning how this occurs. It is concluded that there is a functional dissociation of the cortical inputs, with one class of incoming information comprising purely metric information concerning distance and orientation, probably routed via the grid cells and head direction cells. The other class of information is much more heterogeneous and serves, at least in part, to contextualize the spatial inputs so as to provide a unique representation of the place the animal is in. Evidence from remapping studies suggests that the metric and contextual inputs interact upstream of the place cells, perhaps in entorhinal cortex. A full understanding of the generation of the hippocampal place representation will require elucidation of the representational functions of the afferent cortical areas.     

Attentional reorientation along the meridians of the visual field: Are there different neural mechanisms at play?

Hemispatial neglect, after unilateral lesions to parietal brain areas, is characterized by an inability to respond to unexpected stimuli in contralesional space. As the visual field's horizontal meridian is most severely affected, the brain networks controlling visuospatial processes might be tuned explicitly to this axis. We investigated such a potential directional tuning in the dorsal and ventral frontoparietal attention networks, with a particular focus on attentional reorientation. We used an orientation‐discrimination task where a spatial precue indicated the target position with 80% validity. Healthy participants (n = 29) performed this task in two runs and were required to (re‐)orient attention either only along the horizontal or the vertical meridian, while fMRI and behavioral measures were recorded. By using a general linear model for behavioral and fMRI data, dynamic causal modeling for effective connectivity, and other predictive approaches, we found strong statistical evidence for a reorientation effect for horizontal and vertical runs. However, neither neural nor behavioral measures differed between vertical and horizontal reorienting. Moreover, models from one run successfully predicted the cueing condition in the respective other run. Our results suggest that activations in the dorsal and ventral attention networks represent higher‐order cognitive processes related to spatial attentional (re‐)orientating that are independent of directional tuning and that unilateral attention deficits after brain damage are based on disrupted interactions between higher‐level attention networks and sensory areas.