Estimulación magnética transcraneal para síntomas negativos en la esquizofrenia: una revisión / The transcraneal magnetic stimulation for the negative symptoms in schizofrenia: a review

ABSTRACT

Schizophrenia is one of the most studied diseases in psychiatry and different dysfunctions of thinking, emotions, perception, movement, and behavior converge in it. These dysfunctions affect the quality of life of the patients in different ways. It is a disease that has been observed in the whole world, with a 0.5 to 1.5% prevalence among adults. Although the biological basis of schizophrenia is not clear enough, the dopaminergic hypothesis is preponderant in our understanding of the symptoms of the disease. A mesolimbic pathway hyperactivity is related to a positive symptomathology, while a prefrontal dopaminergic hypofunction relates to negative symptoms. It has been observed that using serotoninergic antagonists, which promote dopaminergic activity in the prefrontal cortex, translates in to a reduction of the intensity of negative symptoms. This negative syndrome includes a difficulty to initiate new activities (apathy), speech and creativity impoverishment (alogia), alterations in emotional expression, and a lack of capacity to experiment joy. Patients with negative symptoms present gray and white matter loss in left-sided cerebral structures, including temporal lobe, anterior cingulated, and medial frontal cortex. Such a loss seems to be more evident in prefrontal regions, such as the dorsolateral prefrontal region, which connects with anterior temporal structures. Persistent negative symptomathology is a concept proposed by Buchanan, which must fulfill the following criteria symptoms are primary to the disease or secondary but have not responded to current treatment; interfere with the patient's capacity to accomplish normal functioning; persist during periods of clinical stability, and represent an unresolved therapeutic need. They must be measurable by clinical scales and persist, at least, six months. The Food and Drug Administration has recently considered negative symptoms as an investigation target or new treatments due to their prevalence and high negative impact in the life of the schizophrenic population. Nowadays, the current treatments available for such an entity are second generation antipshycotics and glutamatergic agents -such as d-cycloserine and glicine-, amisulpiride and seleginine, even though their efficacy is limited. Dysfunction of the human prefrontal cortex is considered to be implicated in the pathophisiology of negative symptoms. This cerebral region is essential in the regulation of emotions and cognition. Multiple neural networks begin in the prefrontal cortex and go towards other cortical association areas, to insular region, thalamic structures, basal ganglia and limbic system. It regulates dopaminergic mesencephalic activity through activating and inhibitory pathways, allowing a precise regulation of dopaminergic activity. This double modulation model of dopaminergic pathways has been recently sustained by studies which prove that extracellular dopaminergic concentration in nucleus accumbens increases or reduces after a high or low frequency stimulation of the prefrontal cortex, respectively. A prefrontal cortex lesion causes a syndrome similar to the negative symptomathology in schizophrenia. Transcraneal magnetic stimulation (TMS) could be effective in the treatment of negative symptoms by activating the prefrontal cortex, maybe by stimulating the liberation of dopamine in the mesolimbic and mesoestriatal pathways which have a crucial role in the pathogenesis of negative symptoms such as apathy and anhedonia. TMS was introduced in 1985 and since the early 90's its potential as a treatment has been tested in numerous neurological and psychiatric conditions. It is a noninvasive means of stimulating nervous cells in superficial areas of the brain. During a TMS procedure, an electrical current passes through a wire coil placed over the scalp. This induces a magnetic field that can produce a substantive electrical field in the brain. This electrical field produces in turn a depolarization of nervous cells resulting in the stimulation or disruption of brain activity. TMS may be applied as a single stimulus or repeated many times per second (repetitive TMS), with variations in the intensity, site, and orientation of the magnetic field. Most research and interest has focused on the potential application of repetitive TMS (rTMS) in the treatment of depression. In addition, in recent years an increasing number of open and double-blinded studies of rTMS were conducted in patients with schizophrenia. Most investigators have chosen to focus on the treatment of specific refractory symptoms or syndromes within the disorder such as refractory auditory hallucinations or persistent negative symptoms. TMS has become widely used in research, especially as a method to probe normal and abnormal brain function, motor cortical physiology, and cognition. Regarding negative symptoms in schizophrenia, eleven studies using TMS were carried out until 2006, with a total of 172 patients studied. These studies are difficult to compare because they used different stimulation parameters and the symptoms described were heterogenic. Six studies were blind and five were open, using high frequency TMS in all of them (frequencies above 1 Hz), which is the type of stimulation most commonly used in treatment studies. Six of these studies found a reduction in the severity of the symptoms, but the reduction was not significant in two of them. Ten were the maximum number of sessions included in every study, except for one, in which 20 sessions of TMS were given. In this study, the score of negative subscale of the PANSS was reduced in 33%, which is considered a significant response, and this result was sustained within the next month. In one of these studies, researchers compared 3- and 20-Hz stimulation with sham stimulation and stimulation provided at the patient's individual alpha frequency. Alpha-frequency stimulation was calculated as the patient's peak alpha frequency from five frontal EEG leads. Stimulation of alpha frequency resulted in a significantly greater reduction in negative symptoms than the other conditions. This finding could suggest that negative symptoms may specifically relate to alpha EEG oscillations, which is interesting and requires further exploration and confirmation. Another two studies were conducted in 2007; in the first one, no improvement in negative, positive of affective symptoms was found. The second one, which was a double-blinded clinical trial, found a significant reduction in the intensity of negative, positive, and general symptoms with the active TMS. We should remark that TMS produces changes in the cortical activity in ventral and dorsoestratial regions, but other cerebral regions could be stimulated too, since some activation abnormalities in the left globus palidus, bilateral caudate nucleus, prefrontal, and temporal right cortex have been found and are associated with the etiology of the negative syndrome. In addition, it will be interesting to see whether changes in subcortical dopamine release, which were shown with rTMS in normal volunteers, can be demonstrated in clinical populations, such as patients with schizophrenia, and how this may relate to response to treatment. There is still a need for a larger number of controlled studies, with larger samples, longer periods of evaluation, and constant stimulation parameters, so they can be compared between them and the exact efficacy of TMS as a treatment for negative symptoms can be established.

RESUMEN

La estimulación magnética transcraneal (EMT) es un método no invasivo que utiliza campos magnéticos alternantes para inducir corrientes eléctricas en el tejido cortical en diferentes áreas cerebrales. Se considera una forma de tratamiento para diferentes trastornos psiquiátricos, especialmente en la depresión, adicciones y esquizofrenia. Está técnica terapéutica ofrece una vía innovadora para estudiar la excitabilidad de la corteza, la conectividad regional cortical, la plasticidad de las respuestas cerebrales y las funciones cognitivas en el estado del enfermo. Aunque se han documentado resultados positivos en la estimulación de la CPF izquierda y en la CPF derecha, se sugiere que puede ejercer su acción beneficiosa a través de diversos mecanismos de acción aún no comprendidos en su totalidad. La corteza prefrontal humana es esencial en el control e integración de las emociones, la cognición y la regulación del Sistema Nervioso Autónomo. Numerosas conexiones neuronales bidireccionales se originan en la CPF y se extienden al resto de las áreas de asociación cortical, región insular, sistema límbico y los ganglios basales. La CPF modula la actividad dopaminérgica mesencefálica mediante una vía activadora y otra inhibidora, lo que permite una regulación sumamente fina de la actividad dopaminérgica. La vía activadora funciona por medio de proyecciones glutamatérgicas directas e indirectas a las células dopaminérgicas. La vía inhibitoria hace lo propio mediante eferencias glutamatérgicas prefrontales a las interneuronas GABAérgicas mesencefálicas y a las neuronas GABAérgicas estriatomesencefálicas. El modelo de la doble modulación del sistema dopaminérgico mesolímbico demuestra que la concentración dopaminérgica extracelular en el núcleo accumbens disminuye o aumenta después de la estimulación de la corteza prefrontal a baja o alta frecuencia, respectivamente. Dentro de los estudios que utilizan la EMT en la esquizofrenia, se ha encontrado que, tras una EMT de alta frecuencia (>1Hz) o repetititiva (EMTr), hay un aumento de la excitabilidad en varias áreas cerebrales, mientras que la excitabilidad cortical disminuye tras una EMT de baja frecuencia (<1Hz). La excitabilidad cortical también depende de la intensidad y duración de la estimulación, lo que quiere decir que a intensidades más altas habrá mayor actividad cortical y a trenes prolongados habrá cambios duraderos en la excitabilidad cortical. Una gama de síntomas de difícil tratamiento en la esquizofrenia son los síntomas negativos persistentes, donde se ha demostrado una disminución de la actividad en la CPF, por lo que la EMT se ha utilizado para revertir dicha hipoactividad y disminuir los síntomas. De forma contraria, los síntomas positivos, como las alucinaciones, se asocian con una hiperactividad de las áreas témporo-parietales y por tanto debería resultar beneficiosa la aplicación de EMT de baja frecuencia en dichas áreas. La EMT de alta frecuencia también se ha utilizado para tratar a sujetos con síntomas catatónicos prominentes y se ha logrado una mejoría con el tratamiento. El objetivo de esta revisión es que se comprendan mejor la EMT y el uso que se le puede dar para tratar diversos síntomas en la esquizofrenia.