Method and device for deep brain stimulation

Abstract

A method of treating Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise in a subject in need thereof, comprising applying a neuromodulation signal to the 1PAG or v1PAG of the subject.

Claims

1. A method of treating Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise in a subject in need thereof, said subject having previously been diagnosed as suffering from Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise, the method comprising applying a neuromodulation signal to the 1PAG or v1PAG of the subject having Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise, wherein the neuromodulation signal has a frequency within the range of 5 to 50 Hz, a stimulus pulse duration within the range of 50 to 450 microseconds, a balanced biphasic waveform with zero net charge flow, and at least one of a stimulus pulse voltage within the range of 1 to 5 volts or a stimulus pulse current within the range of 1 to 5 mA sufficient to stimulate the 1PAG or v1PAG.

2. The method according to claim 1, wherein the method is a method of treating vascular brain disorders where there is small vessel compromise in a subject in need thereof, and wherein the vascular brain disorders comprise vascular dementia and/or small vessel disease and/or multiple stroke disease and/or post-haemorrhagic vasospastic disease and/or moyamoya disease.

3. The method according to claim 1, wherein the method includes implanting an electrode lead wire unilaterally into one hemisphere of the brain of the subject to a depth level with the superior colliculus of the subject, the applying of the electrical pulsed signal to the 1PAG or v1PAG of the subject being via said electrode lead wire.

4. The method according to claim 3, wherein the method includes externalising the electrode lead wire for a transient period of stimulation and/or connecting the electrode lead wire to a RF-receiver buried in the skull and/or connecting the electrode lead wire to a pulse-generator implanted in the skull.

5. The method according to claim 3, further including applying a further neuromodulation signal to the medial thalamus and/or fornix and/or anterior nucleus and/or the centromedian parafascicular nuclei of the brain of the subject, said further neuromodulation signal being a high frequency signal, and wherein said electrode lead wire is inserted so as to traverse the medial thalamus and/or fornix and/or anterior nucleus of the brain of the subject, and said further neuromodulation signal is applied to said medial thalamus and/or fornix and/or anterior nucleus and/or the centromedian parafascicular nuclei.

6. The method according to claim 3, further including implanting a further electrode lead wire into said one hemisphere, and applying another electrical signal to said further electrode lead wire.

7. The method according to claim 6, wherein the another electrical signal is applied to the medial thalamus and/or fornix and/or anterior nucleus and/or the centromedian parafascicular nuclei of the brain of the subject.

8. The method according to claim 3, further including implanting a further electrode lead wire into the other hemisphere of the brain of said subject to a depth level with the superior colliculus thereof, and applying another electrical pulsed signal to said further electrode lead wire.

9. The method according to claim 1, further including applying a further neuromodulation signal to the medial thalamus and/or fornix and/or anterior nucleus and/or the centromedian parafascicular nuclei of the brain of the subject, said further neuromodulation signal being a high frequency signal.

10. The method according to claim 9, wherein said further neuromodulation signal is a further electrical pulsed signal.

11. The method according to claim 1, further comprising the step of selecting the subject for treatment based on the subject having a diagnosis of Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise in said subject.

12. A method of treating Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise in a subject in need thereof, said subject having previously been diagnosed as suffering from Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise, the method comprising: applying a neuromodulation signal to the 1PAG or v1PAG of the subject having Alzheimer's Disease and/or Multiple Sclerosis and/or Minimally Conscious State and/or Mood Disorders and/or vascular brain disorders where there is small vessel compromise, wherein the neuromodulation signal has a frequency within the range of 5 to 50 Hz, a stimulus pulse duration within the range of 50 to 450 microseconds, a balanced biphasic waveform with zero net charge flow, and at least one of a stimulus pulse voltage within the range of 1 to 5 volts or a stimulus pulse current within the range of 1 to 5 mA sufficient to stimulate the 1PAG or v1PAG; applying a further neuromodulation signal to the medial thalamus and/or fornix and/or anterior nucleus and/or the centromedian parafascicular nuclei of the brain of the subject, wherein said further neuromodulation signal has a frequency greater than 70 Hz, a stimulus pulse duration within the range of 25 to 350 microseconds, a balanced biphasic waveform with zero net charge flow, and at least one of a stimulus pulse voltage within the range of 1 to 3 volts or a stimulus pulse current within the range of 1 to 5 mA sufficient to stimulate at least one of the [1PAG or v1PAG] medial thalamus, fornix, anterior nucleus, or the centromedian parafascicular nuclei.

Description

FIGURES

(1) FIG. 1 shows the blood flow response in the electrode side of the brain with low frequency PAG stimulation applied unilaterally measured using a C-11 diprenorphine tracer in five subjects.

(2) FIG. 2 shows the blood flow response in the non-electrode side of the brain with low frequency PAG stimulation applied to the contralateral hemisphere.

(3) FIG. 3 shows the change in blood flow across particular regions of the brain when PAG stimulation is switched on.

(4) FIG. 4 shows an MRI scan of a typical straight-line trajectory with the electrode spanning the two targets of the medial thalamus and the PAG.

(5) FIG. 5 is an illustration highlighting the key structures in FIG. 4.

(6) FIG. 6 shows an electrode lead wire adapted for dual target stimulation comprising two active regions of electrodes which are approximately aligned with the two targets.

(7) FIG. 7 illustrates an arrangement of a directional lead according to this invention that has three ring electrodes at proximal and distal electrode groups in which the central ring electrodes are divided into three segments to provide radial directionality.

(8) FIG. 8 illustrates an alternative arrangement of a directional lead in which the distal and proximal electrode groups each consist of four rows of semi-circular ring electrodes.

(9) FIG. 9 is an enlargement of part of the electrical lead wire illustrated in FIG. 8.

(10) FIG. 10 shows positioning of the implantable pulse generator in a pocket in the frontal-parietal region of the skull and typical unilateral lead placement.

(11) FIG. 11 is a flow-chart illustrating an implantation method employing a skull mounted IPG and implantation of electrode lead-wire(s).

DESCRIPTION

(12) We implanted a case series of five patients with electrodes implanted unilaterally into the v1PAG for chronic neuropathic pain using magnetic resonance image directed localisation (Patel et al., unpublished data). Three of these patients also had electrodes implanted into ventromedian/parafascicular complex (CMPf) and one into the ventro-posteriolateral nucleus of the thalamus. Neuromodulation of the v1PAG employed a low frequency signal of frequency of between 5 and 10 Hz, forward pulse width 90 to 180 microseconds and amplitude 1 V to 4.3 V. In all cases a balanced biphasic waveform was employed with zero net charge flow. Blood flow across the brain was measured through functional imaging of the rate of uptake of a C-11 diprenorphine tracer into tissue (KO using Positron emission tomography (PET).

(13) Unilateral PAG-DBS resulted in bilaterally increased blood flow to the whole brain; no lateralised effect was noted. In response to the suggestion that this finding may be a consequence of the methodology, baseline measures of 3 healthy volunteers undergoing PET scanning (using the same process) did not show increased blood flow. In fact, the difference in whole brain blood flow between DBS patients and healthy volunteers approached significance in this small sample. In any case, an increase in mean arterial pressure should not alter cerebral blood flow, which would be maintained by autoregulation.

(14) FIG. 1 shows the blood flow response to neuromodulation of v1PAG in the hemisphere of the brain in which the electrode was implanted. With stimulation turned on, all subjects exhibited an increase in brain perfusion throughout the hemisphere. Averaged over five DBS subjects, the increase in blood perfusion between stimulation on and off was just less than 14% (p=0.001).

(15) FIG. 2 shows the blood flow response in the non-electrode hemisphere of the brain. It is interesting to note that perfusion in the non-electrode hemisphere also increased by a similar amount (circa 14%) when v1PAG stimulation was switched on in the contralateral hemisphere.

(16) Unilateral PAG-DBS resulted in significant bilateral increased blood flow to the PAG and anterior cingulate cortex. Again, no lateralised signature was seen. This is in keeping with the contralateral projection fibres within the PAG and the spread of electrical stimulation beyond the electrode tip. Consequently, we would expect PAG to exert its analgesic effect on both the contralateral and ipsilateral sides of the body, which has been described previously (Levy et al, 1987).sup.21.

(17) Referring to FIG. 3, other regions demonstrated non-significant increases in blood flow in response to PAG-DBS, namely the nucleus accumbens, subgenual anterior cingulate, hippocampus, insula, caudate, cerebellum, and the occipital lobe, with 10-15% increases in blood flow in these structures; although it is of interest to note that blood flow did not increase in the thalamus.

(18) This increase in brain perfusion may be responsible for the known anti-hypertensive effect of v1PAG modulation. Increased blood flow within the brainstem may be expected to result in a centrally-driven and sympathetically-mediated decrease in blood pressure to autoregulate brain perfusion and reduced demands on the heart.

(19) We believe that the 1PAG may also be an effective target for increase in brain perfusion, either alone or in combination with the v1PAG. In reality, the current path around the electrode site tends to be dispersed and therefore it is unlikely that these two structures can be exclusively targeted.

(20) One aspect of this invention is therefore neuromodulation of the 1PAG and/or v1PAG as a treatment for early and late stage Alzheimer's disease, with a method that involves unilateral neuromodulation of the 1PAG and/or v1PAG resulting in increased perfusion across the entire brain. Unilateral stimulation of the right hemisphere would be preferred for Alzheimer's disease, as this is implicated in affective, cognitive function and memory storage in the majority of patients; and is non-dominant for speech function.

(21) Neuromodulation of the PAG may provide a treatment for neurological conditions other than Alzheimer's disease, for example in multiple sclerosis autonomic dysfunction and perfusion disturbances globally and within cortical demyelinating plaques are well documented, and would likely benefit from PAG stimulation.

(22) Neuromodulation of the PAG may also be combined with other targets. The dorsomedial nucleus of thalamus along with the midline nuclei act as a relay for inputs from a number of brain areas such as the solitary nucleus, substantia nigra reticulata, amygdala and ventral pallidum. The dorsomedial nucleus projects to the prefrontal cortex and the limbic system which is associated with attention, motivation, formation of long-term memory and sense of smell. The medial dorsal nuclei are also involved in processing pain. Neuromodulation of the dorsomedial nucleus may therefore be used to alter emotional response and memory. High frequency modulation of the dorsomedial nucleus and/or anterior nucleus may serve to improve memory formation.

(23) Therefore, another aspect of this invention is combined neuromodulation of the 1PAG and/or v1PAG and dorsomedial nucleus and/or midline nuclei as a treatment for early and late stage Alzheimer's disease. In combination, simultaneous low frequency modulation of the 1PAG and/or v1PAG and high frequency neuromodulation of the dorsomedial nucleus and/or midline nuclei will serve to increase perfusion of the hippocampus and other important structures involved in cognition and memory.

(24) These two targets may be addressed by implanting two electrode lead wires unilaterally, one targeting the 1PAG and/or v1PAG and the other the dorsomedial nucleus and/or midline nuclei. Localisation may be achieved by any of the known methods for targeting deep brain stimulation electrodes, but image guided implantation is preferred. More preferably, according to this invention, a single electrode lead-wire is used to address both targets, so as to minimise both surgical time and risk employing image based guidance to accurately target both centres with the single lead.

(25) The medial surface of the thalamus forms the upper part of the lateral wall of the third ventricle. The preferred straight-line trajectory for an electrode lead-wire that encompasses both the medial thalamus and the PAG has an entry point in the frontal-parietal region of the skull and a trajectory that traverses the ventricle. FIG. 4 is a MRI scan of a section of the brain showing a straight line trajectory of an electrode, 41, traversing the medial thalamus proximally and the PAG distally. Optionally, a permanently implanted catheter may be used as a guide tube for the electrodes to assist the transventricular approach, such as that described by Gill in “A neurosurgical guide device” GB2357700B.

(26) FIG. 5 is an illustration that identifies the key structures involved. FIGS. 4 and 5 are slices at an angle through the head indicated by the cross section line 51. The lead, 52, follows a straight line trajectory from the burr hole and optional cap, 57, through the lateral ventricle, 53, into the medial thalamus, 54, bypassing the third ventricle, 56 into the PAG, 55.

(27) According to this invention, high frequency modulation is applied to the medial thalamus to inhibit neurons in structures such as the dorsomedial nucleus, anterior nucleus and centromedian/parafascicular complex. This inhibitory high frequency modulation is a train of pulses of forward pulse width 25 to 350 microseconds, more preferably 60 to 90 microseconds, at a repetition frequency of greater than 70 Hz, more preferably in the range 100 to 200 Hz, or 130 or 150 Hz. The forward (negative going) pulses are delivered at amplitude of typically 1 or 2 to 3 or 5 mA with a current controlled output or 1 to 3 V with a voltage controlled output with a balancing reverse charge typically delivered at the same or lower intensity.

(28) Also according to this invention, low frequency modulation is applied to the 1PAG and/or v1PAG. Low frequency modulation consists of a train of pulses of forward pulse width 50 to 450 microseconds, at a repetition frequency of 5 or 10 to 40 or 50 Hz, typically 90 to 180 microsecond pulses of 1 or 2 to 3 or 5 mA amplitude with a current controlled output, or 1 to 5 V amplitude with a voltage controlled output. As before, a balancing reverse charge is required. Preferably the repetition frequency is 5 to 10 Hz or 20 Hz, however in some instances response is maximised at 40 Hz. This stimulatory low frequency modulation acts to excite neuronal activity in the 1PAG and/or v1PAG.

(29) A further aspect of this invention is optimization of the relative intensity of the high and low frequency modulation and the frequency of each modulation within their respective bands to optimise therapy; these are applied either continuously or in bursts, the latter which may be more physiologically representative.

(30) Separation between the centres of the two targets varies, but is typically 15 mm as illustrated in FIG. 5. One aspect of the device is that the distal end of the electrode lead-wire should comprise two regions of active electrodes separated by a gap between the centre of each region of 10 or 12 or 15 or 17.5 or 20 mm. This ensures that the two regions of active electrodes are approximately aligned with the respective targets. The upper region of active electrodes (proximal electrodes) is aligned with the target in the medial thalamus. The lower region of active electrodes (distal electrodes) is aligned with the 1PAG or v1PAG.

(31) The respective high and low frequency modulation pulse trains are typically interlaced and applied to the proximal and distal electrodes. If electrical neuromodulation is used, preferably, the two pulse trains should be applied in a manner that ensures that there is no risk of cross flow of currents flowing between electrodes in the high and low frequency regions of the active electrodes.

(32) This can be achieved by two means: (i) The output circuit is configured such that the output circuits in the implantable pulse generator (IPG) for the high and low frequency modulation are provided with galvanic isolation from each other by means of transformer or capacitive coupling between the power supply and output circuits. (ii) A contention circuit is provided in the implantable pulse generator (IPG) that ensures that the pulses in the high and low frequency modulation do not overlap in time. The contention circuit reschedules the output of one of the contending pulses until the other contending pulse has completed. Preferably pulses comprising the high frequency modulation are prioritised over those comprising the low frequency modulation so that the relative jitter on the pulse trains is minimised as a percentage of the overall mark-space ration of the pulse train.

(33) Also according to this invention, using a single electrode lead wire of the type disclosed 1PAG and/or v1PAG modulation may be combined with other targets associated with memory such as the fornix, provided a trajectory can be located that encompasses both the proximal target associated with memory and cognition and the distal 1PAG and/or v1PAG.

(34) Preferably, accurate positioning of the electrode lead-wire to address both targets with a single electrode lead wire is aided by Magnetic resonance imaging (MRI) guidance, optionally with Diffusion tensor imaging (DTI) to provide visualization of the neural tracts. Even with the benefit of this technique, lead placement may be optimised after implantation by sensing of local field potentials (LFPs) in order to identify the target accurately. The characteristic LFP rhythms that can be employed for targeting vary by condition, for example AD and depression tend to be associated with theta and delta rhythms in the medial thalamus respectively.

(35) Additionally, it may be desirable to exclude certain stimulation locations and directions, in particular those associated with visual sensory feedback by looking for saccade-related (eye movement) LFPs which will assist confirmation of depth within the PAG and enable choice of optimal contact/s above this zone whilst avoiding any eye-related side-effect. The risk of anxiety as a side-effect may be reduced by avoiding lateral and dorsal directions. In order to facilitate this, a lead with directional capability may be desirable.

(36) In summary, one aspect of this invention is a device and a method of treatment of Alzheimer's disease utilising dual frequency/dual target neuromodulation with a single lead implanted traversing the medial thalamus or the fornix into the 1PAG and/or v1PAG to a depth level with the superior colliculus with high and low frequency modulation applied to the respective targets.

(37) In the treatment of hypertension using low frequency DBS of the 1PAG and/or v1PAG, an increase in repetition frequency from typically 5 to 40 Hz and increase in amplitude of the applied stimulus produces a corresponding greater reduction in resting blood pressure. However, an increase in frequency or amplitude may be associated with side effects caused by leakage of current to nearby structures, such as anxiety. With dual target stimulation of the medial thalamus and PAG using a single lead adapted to modulate both targets, high frequency modulation of the medial thalamus may be used to suppress the emotional response generated by leakage of low frequency currents from the region of the 1PAG and/or v1PAG.

(38) In non-hypertensive subjects modulation of the 1PAG and/or v1PAG does not materially affect resting blood pressure because these individuals do not exhibit increased sympathetic activity in the resting state.

(39) Preferably the electrode lead-wire should be implanted unilaterally and in the non-dominant hemisphere of the brain. The non-dominant hemisphere is normally the right side, contralateral to the side that primarily controls speech processing.

(40) In respect of pain, preclinical data demonstrates the role of the parafascicular complex in the medial thalamus in nociception (Shi et al 2011).sup.22. The dorsomedial nucleus and the centromedian/parafascicular complex are in close proximity, with the dorsomedial nucleus promixal to the entry point using the transventricular trajectory contemplated in this invention. This allows the proximal electrodes in the electrode lead-wire described herein to modulate either the dorsomedial nucleus or centromedian/parafascicular complex, or both. The electrode lead-wire is preferably implanted in the hemisphere contralateral to the site of pain.

(41) A case series of four subjects were implanted at North Bristol NHS trust with the PVG/PAG modulated at 10 Hz and the dorsomedial nucleus and/or centromedian/parafascicular complex modulated at 132 Hz. Modulation of the PAG produced a sensation of warmth, a reduction in cold pain threshold and 70% reduction in pain. Modulation of the dorsomedial nucleus/centromedian/parafascicular complex resulted in paraesthesia (a tingling sensation) over the painful region, an 80% reduction in pain and reported telescoping of phantom limb. Modulation of both targets simultaneously produced a greater reduction in allodynia scores and overall pain score than individual targets alone. The mechanism of action is not fully elucidated but may be that PAG modulation gates noxious stimuli via descending opioid projection, while also projecting to supratentorial structures. Parafascicular complex stimulation modulates sensory input via the thalamus and projects to the nucleus accumbens causing a reported sensation of dissociation from the pain in subjects.

(42) Therefore, also according to this invention low frequency modulation of the PVG/PAG at less than 40 Hz or 50 Hz and high frequency modulation of the dorsomedial nucleus and/or centromedian/parafascicular complex at greater than 70 Hz, 80 Hz, 90 Hz, 100 Hz or 130 Hz may be employed using either two electrodes implanted unilaterally or a single electrode adapted for dual target stimulation also implanted unilaterally.

(43) In two patients implanted with electrodes in the dorsomedial nucleus and v1PAG, modulation of the v1PAG produced an immediate reduction in anxiety. As discussed, modulation of the dorsomedial nucleus is implicated in emotional response and therefore combination of the two targets is a promising treatment for medically refractory depression employing a single electrode implanted unilaterally in the right hemisphere of the brain. The PET blood flow results disclosed above further augments this theory with increased perfusion observed in the subgenual cingulate gyrus, dorsal cingulate gyrus, nucleus accumbens, amygdala and insula.

(44) A short form Profile of Mood States (POMS-SF) developed by Shacham (1983) was used to assess mood changes in the case series of five patients at North Bristol NHS trust with PAG stimulation on and off. Table 1 summarises these results. Significance was tested using a two tailed paired t-test, improvement in all mood scores from PAG stimulation was observed. While changes in subset scores other than Anxiety were not significant in this small case series, the total POMS results indicates a substantial and significant improvement associated with PAG stimulation.

(45) TABLE-US-00001 TABLE 1 POMS Subset Score % change with DBS on p Anxiety −45.0% 0.001 Depression −14.3% 0.37 Anger −11.1% 0.37 Vigour +20.7% 0.30 Fatigue −48.4% 0.10 Confusion −46.7% 0.08 Total POMS −73.6% 0.008

(46) Depression is associated with functional insufficiency of the right hemisphere combined with its physiological over-activation, such that unilateral right PAG stimulation would be preferred, especially with PET blood flow results showing increased ipsilateral perfusion within the subgenual cingulate, amygdala and insula, and bilaterally in the nucleus accumbens.

(47) Patients often present with combined hypertensive and chronic pain syndromes. As observed by Olsen et al 2013, these conditions may be linked. A case series of three patients with pain and hypertension were implanted with dual stimulation in the medial thalamus and v1PAG. In all cases, a reduction in resting blood pressure, pain and anxiety has been observed; a ‘virtuous circle’ in which reduction in pain and anxiety may lead to further reduced in blood pressure. With the electrode lead-wire described in this invention, a single unilateral procedure may be employed to treat the condition, minimising cost, surgical time and risk to the patient.

(48) There are other neurological conditions in which dual target stimulation of the thalamus and PAG may be effective. For example persistent vegetative and minimally conscious states (disorders of consciousness) may be treated by a method comprising dual target stimulation of the medial thalamus and the PAG, which may prove to be more beneficial than stimulation of a single target alone.

(49) In the treatment of epilepsy, stimulation of dual targets unilaterally or bilaterally with combinations including the anterior nucleus and CM-PF, or anterior nucleus and PAG, or CM-PF and PAG may produce a generalised cortical synchronisation, reducing the abnormal cortical excitability that underlies epilepsy. Stimulation may be provided continuously, intermittently or in response to sensed abnormality in cortical activity.

Electrode Lead Configuration

(50) If PAG stimulation only is required typically four contacts are sufficient to provide coverage of the target while providing adjustment to compensate for positional deviation from the target along the axis of the lead. Such electrode lead wires are in common use in DBS surgery and consist a cylindrical electrode lead wire of typically 1.3 mm diameter with four cylindrical contacts at the distal end each of between 1 to 3 mm in length separated by gaps of 0.5 to 2 mm.

(51) A directional electrode lead may be preferred in order to provide a degree of radial selectivity to more accurately focus stimulation towards the target in the case of lateral displacement of the lead from the desired target. Directional electrodes are desirable in order to optimise therapy delivery while minimising disturbance of nearby nuclei and fibre tracts, potentially reducing side effects. Certain types of directional electrodes are known in the art as described by Hegland et al “Implantable lead with multiple electrode configurations” US20080269854 and Moffitt et al “Deep brain stimulation current steering with split electrodes” US20100268298.

(52) For dual targets addressed by a single non-directional electrode lead wire as contemplated in this invention, two active regions each of typically four contacts are provided, separated by a gap so that the active regions are located with their centres separated so that the active regions are approximately aligned with the two targets. For a combination of medical thalamus and PAG neuromodulation as previously described, separation varies by individual but is approximately 15 to 20 mm.

(53) An electrode lead adapted as described is illustrated in FIG. 6. The lead at its distal end comprises a group of four cylindrical electrodes (63) separated by a gap (62) and four cylindrical electrodes at the proximal end (61). In this embodiment the separation between proximal and distal electrode groups is 17.5 mm between centres and the electrodes are 1.5 mm in length separated by insulated gaps of 0.5 mm. Accordingly the lead illustrated is suitable for stimulating targets which are separated by 11.5 to 23.5 mm between centres.

(54) Variation of electrode pitch/gap and separation between targets may dictate the use of other separation between distal and proximal electrode groups, but typically the range is 5 to 30 mm, more preferably 8, 10, 15, 20 or 25 mm. Four electrodes in each electrode group are normally sufficient, but any number from one upwards may be employed.

(55) FIG. 7 illustrates an arrangement of a directional lead according to this invention. The lead comprises three cylindrical electrodes in the proximal (71,72,73) and distal (75,75,76) electrode groups separated by an insulated separator (74). In this embodiment the centre electrode of each electrode group is split into three radial segments each covering an arc of 100 degrees with a 20 degree insulator between each segment. The arrangement of the segmented annular electrode is shown by section A-A of FIG. 7.

(56) Ideally a directional lead should have the minimum number of controllable electrodes consistent with achieving the desired level of directionality. The reasons for this are that fewer electrodes minimizes the number of wires in the lead and minimizes the complexity of the connection between lead and IPG and the hermetic feed-through in the IPG itself. Perhaps most important, there is a minimum electrode area for a particular forward (typically negative going) charge level at which the metal species in the electrode do not migrate into the tissues, above which there are risks of long term electrode decomposition and toxicity. This consideration favours directional leads with fewer, larger electrodes.

(57) The lead illustrated in FIG. 7 provides translation of the electrical field both in radial and axial directions at each of the distal and proximal groups. This translation is provided by selecting the appropriate electrode to act as cathode in an electrode pair consisting of a cathode and one or more anodes.

(58) Conventionally, electrical neuromodulation employs a negative pulse of desired pulse width and current or voltage applied to the cathode, followed by a balancing reverse charge to ensure that the net charge delivery is zero. In combination with the pulse charge limit mentioned above, zero net charge is important to ensure that ionic species generated at the electrode tissue interface during delivery of the forward charge are recombine during the reverse charge. This balancing charge is typically delivered at the same or lower current or voltage than the forward charge, either by means of an active recharge at a lower current for a proportionally longer duration as required or by discharge of series capacitors in the output circuit. In the electrode lead in FIG. 7, radial control is provided by always recruiting the central electrode as either anode or cathode. For example, in the case where one of the outer of the three electrodes is cathode, selection of one of the three central radial contacts will cause current to tend to flow in the tissues on that side of the electrode.

(59) The lead arrangement in FIG. 7 has the advantage that it requires only ten connections to the IPG. A further saving in connections can be made by connecting the outer ring electrodes 73+75 in parallel, similarly with 71+77 (or 77+73 and 75+71), multiplexing the electrodes. This reduces the overall number of connections to the IPG to just eight. In practice, with such a multiplexed arrangement there is some cross leakage of current between shared electrodes but this is minimal because of the close proximity of the nearby anodes and cathodes in each electrode group ensures that there is lower resistance between electrodes in each group and therefore the majority of current flows within the group.

(60) Further refinement of the applied electrical field to improve control of the effective point at which neuromodulation is delivered to the tissues both in non-directional and directional electrodes described herein may be obtained by modulating the pulses applied to multiple electrodes as described by Gillbe in “Array Stimulator” U.S. Pat. No. 8,612,018 B2, or by sharing current between the electrode using multiple current sources as described by Woods et al “Implantable generator having current steering means” U.S. Pat. No. 6,909,917 B2.

(61) An alternative arrangement of segmented electrodes in presented in FIG. 8. In this example the distal and proximal electrode groups each consist of four rows of semi-circular cylindrical electrodes (81, 83), each covering a 180 degree arc, separated by a gap 83. This arrangement requires sixteen connections to the IPG if no electrodes are multiplexed. A variation of this arrangement, consisting of three rows of segmented electrodes requires 12 connections to the IPG.

(62) The distal group is presented enlarged in FIG. 9. The semi-circular segments comprising each ring electrode are displaced from the adjacent electrode(s) by 90 degrees. With this arrangement, it is possible to achieve an approximate 90 degree directional resolution by selecting the desired cathode (the active electrode) and anode in the adjacent ring electrode. For example, selection of electrode 91 as cathode and 92 as anode will cause the electric field to have it centre in the approximate region denoted by the “X” in FIG. 9, whereas recruitment of a second anode 93 will cause the field to spread out along the longitudinal axis of the lead and be centred half-way along the axis of electrode 91.

(63) The arrangements described in FIGS. 7 and 9 are ideal for the leads that are designed for neuromodulation of the 1PAG and/or v1PAG such as contemplated in the first, second and third aspects of the invention described above wherein the distal electrode group is omitted. In this case, only five and eight connections respectively are required to the IPG.

Device and Implantation

(64) A feature of the implantable pulse generator (IPG) contemplated in this invention is that the IPG is generally more compact that conventional devices as it may require only a single electrode lead wire with relatively few contacts. Furthermore, unilateral implantation in the non-dominant hemisphere of the brain as described in various aspects of this invention simplifies the procedure and reduces the possibility of undesirable side effects.

(65) This arrangement is ideal for a skull mounted IPG implanted in a pocket local to the burr-hole through which the electrodes are routed into the brain. In order for this to be feasible, the IPG should be of the order of 7 cc-8 cc or less and 6 mm-7 mm or less in thickness, approximately one third of the volume of a conventional IPG which would be normally implanted in a chest cavity. Implantation can be achieved by means of a single incision encompassing the region surrounding the burr hole and the IPG pocket. Only a short electrode lead wire is required, preferably less than 40 cm and more preferably less than 30 cm or 20 cm. A short lead wire provides the benefit that the system will be less sensitive to induced currents leading to heating of the electrode/tissue interface during magnetic resonance imaging and the standardised procedure means that this heating can be more reliability characterised by testing prior to implantation.

(66) A skull mounted IPG is therefore the preferred type of device contemplated in this invention but conventional devices may also be employed. Skull implantation permits the procedure to be conducted in one step without removing the stereotactic frame used to position the electrode, which would normally be necessary before repositioning the patent to tunnel electrodes to an IPG site in the chest. Elimination of this step reduces surgical time and reduces risk of infection. Elimination of leads in the neck is beneficial as tissue erosion, discomfort and subsequent movement limitations are is not uncommon in this highly mobile region. The implantation procedure can be completed in a single-stage in three hours or less compared with five to six hours with a conventional IPG.

(67) An arrangement for a skull mounted IPG is illustrated in FIG. 10. The IPG, 101, sits in a skull pocket, 102, and is connected to an electrode lead wire, 104, which is routed via a burr hole and optional cap, 106, held securely in place with a lead fixation, 105. The internal placement of the electrodes has been previously discussed as illustrated in FIGS. 4 and 5. In the bilateral case, two lead wires are connected to a single IPG.

(68) There are many established procedures for implantation of DBS electrodes, the surgical procedure illustrated in FIG. 11 is one such method that employs image guidance and a catheter used as a guide tube to place the electrodes under general anaesthesia.

(69) Prior to or at admission, the patient receives a high resolution MRI scan and post contrast volume scan (highlighting blood vessels) for planning. In advance of the day of surgery, the neurosurgeon plans the entry point and trajectory to span the target sites.

(70) Referring to FIG. 11, on the day of surgical intervention and under general anaesthesia a reference frame is applied and a CT scan is taken with contrast (to identify blood vessels). The high-resolution pre-operative MRI scan and CT scan are fused on planning software, referencing the pre-planned target position relative to the reference frame. 3D co-ordinates are input into the stereotactic frame.

(71) An incision is made on the top of the head encompassing the planned burr hole and IPG pocket site as illustrated in FIG. 10 (or two smaller incisions at the IPG site and burr hole). A burr hole is formed and a guide tube is implanted, and a stylette is introduced down the guide tube to the planned depth, just short of the proximal target. A second burr hole and guide tube may be implanted if desired for bilateral electrodes and the lead tunnelled the short distance under the scalp to the second site.

(72) Sub-millimetre precision at the desired target is necessary to optimise the treatment and avoid side effects. Intra-operative CT enables verification of accurate target localisation. The stylette is withdrawn and the lead inserted down the guide tube to the measured depth encompassing both proximal and distal targets in the case of dual targets. The lead is then secured to the skull with an anchoring device such as a titanium plate (FIG. 10, 105).

(73) A pocket of the IPG dimensions is formed in the frontal-parietal region of the skull. This is machined using a burr and a template to the appropriate depth. The device is secured to the skull with a custom plate, leads are connected and secured and the incision(s) are closed.

(74) This technique typically requires a single pass, is carried out entirely under general anaesthesia and is safer and more accurate than currently established techniques.

(75) A robot may be employed to assist in implantation. In this case the robot may be referenced to fiducials attached to the patient's skull. The robot provides 3D positional guidance for the surgeon when drilling the burr hole and introducing the electrode in the desired trajectory. In a more sophisticated application, the robot may drill the burr hole, introduce the catheter to the planned depth and machine the pocket for the skull mounted IPG.

(76) For treating disease such as post-haemorrhagic vasopasm, where the duration of the condition is short-lived and whilst the patient group is being treated on the intensive care unit, it would be feasible to have the lead externalised and connected to an external pulse generator; or the lead connected to a RF-receiver is implanted into the skull.

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