Transcranial magnetic stimulation for small animals

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The present invention provides a positioning device (1) for positioning a transcranial magnetic stimulation coil (15). The positioning device (1) comprises a support element (4) adapted for implantation at a cranial stimulation site of an animal, and at least one protrusion (6) connected to the support element (4) for extending transdermally when the support element (4) is implanted. The at least one protrusion (6) is adapted for mechanically connecting with the transcranial magnetic stimulation coil (15) for administering transcranial magnetic stimulation at said cranial stimulation site of said animal. In a further aspect, the invention provides in a kit of parts comprising such positioning device (1) and a transcranial magnetic stimulation coil (15). Such kit of parts may further comprise a stimulation pulse source (21) for supplying a pulsed electrical signal to the transcranial magnetic stimulation coil (15).

The present invention relates to the field of magnetic neurostimulation. More specifically it relates to transcranial magnetic stimulation of small animals, for example for preclinical research.

Transcranial magnetic stimulation (TMS) is a non-invasive technique which makes use of a rapidly varying magnetic field applied to a position on the head in order to induce electrical currents in the brain. The induced currents may cause an activation or inhibition of specific areas of the brain. TMS may be applied for diagnostic purposes, e.g. for functional mapping of the human cortex or for diagnosis of demyelinating diseases such as multiple sclerosis, by measuring the latency time between activation of the motor cortex by single pulse TMS and the response in the muscle detected by electromyographic measurements.

More recently, repetitive TMS (rTMS) has been used in the treatment of diverse chronic neurological and psychiatric disorders, such as addiction, migraine, tinnitus and epilepsy. Furthermore, rTMS has been FDA-approved since 2008 for the treatment of depression. Development of non-pharmaceutical and non-toxic treatment for neurological disorders is a growing area of research, as in 20-30% of the patients having such brain disorders the current pharmaceutical treatments may not prove effective and in an additional 20-30% of the patients such pharmaceutical therapy may be suboptimal or may have significant side-effects.

Although rTMS is a non-invasive and easily applicable form of therapy which has yielded promising clinical results, the therapeutic potential of rTMS remains underused due to limited knowledge about the optimal stimulation parameters, optimal stimulation target in the brain, optimal TMS coil design and generally insufficient knowledge of the working principles and effects of rTMS.

The choice of currently used stimulation parameters in human applications is up until now primarily based on trial and error. Stimulation is mostly applied at frequencies between 1 Hz and 25 Hz, and this has remained unchanged since the initial studies about the use of TMS. However, a large margin for improvement may exist for the stimulation frequency. For example, for another form of neural stimulation, deep brain stimulation (DBS), it has been found that stimulation frequencies above 100 Hz, or random frequency stimulation, induce a stronger effect than the conventionally applied low frequencies. Furthermore, the choice of dimensions and shape of the TMS coil for the treatment of patients is primarily based on empirical findings. Figure-eight shaped or circularly shaped coils are typically preferred. Nevertheless, it is known that the number of windings, the number of loops, the wire gauge, the material composition, the conicity of the coils, etc. may influence to a large extent the focality of the induced electrical field and hence neurophysiological response.

Since human research into optimization and working principles is limited due to ethical considerations and the necessity of large and homogenous groups of patients, preclinical research in which TMS is applied to experimental animals may be crucial in gaining a more thorough understanding of TMS. However, the currently commercially available TMS stimulators are intended for use in human patients or test subjects and the focus of the field of such stimulators may therefore be inadequate for accurately stimulating targeted brain areas in these small animals. Such stimulators may furthermore only offer limited flexibility regarding the choice of stimulation parameters such as pulse width, frequency, stimulation pattern, intensity and total stimulation time, e.g. may only offer a limited range of such parameters only consistent with currently known clinical paradigms in humans, but not suitable for extensive experimentation and protocol optimization.

In D. Liebetanz et al, "Safety aspects of chronic low-frequency transcranial magnetic stimulation based on localized proton magnetic resonance spectroscopy and histology of the rat brain," Journal of Psychiatric Research, volume 37 (2003), pages 277-286, a transcranial magnetic stimulation coil and stimulator specifically adapted for small mammals are disclosed. It is however an important disadvantage of the system there disclosed that positioning the coil on the animal head in a reproducible way may be difficult. This could lead to variable results due to the absence of focus on the brain target region in small mammals hence limiting the translational validity towards human applicability. Also in such system it may be impossible to apply TMS to small mammals that are awake and freely moving, which implies that no behavioural or unsedated imaging monitoring can be performed.