These concepts are based on years of experience in the field published in the international litterature.
Anatomy of target areas
The brain maps of the atlas of Dr. Morel (Multiarchitectonic Stereotactic Three-dimensional Atlas of the Human Thalamus and Basal Ganglia) allows high-precision localization of selected millimeter-large target areas in the brain.
Physiology of the brain hemispheres
There is accumulating evidence that the brain functions as an oscillating coherent generator. The most important partners are the cortical areas and the thalamus, which is a nucleus, or cell group, in the middle of the brain hemisphere. There are numerous (many billions) recurrent connections (or loops) from thalamus to cortex and back as well as between cortical areas. This complex organization may be compared to an orchestra, with the thalamus in the middle as conductor and the cortical areas distributed around as the players. Every sector of this orchestra, sensory, motor and mental (cognitive/emotional), has a dual organization, with tightly organized executing and diffusely organized modulating components. This thalamocortical system, or network, possesses the neuronal anatomo-physiological organization to function as a coherent oscillator. It could in addition harbour complex non-linear, chaotic, or even quantum-physical properties.
The neurophysiological research of the last 30 years brought indeed strong evidence that every brain function correlates with the production of an adequate rhythmicity. This rhythmicity has as basis the neuronal loop which connects reciprocally corresponding parts of the thalamus and cortex, the so-called thalamocortical loop. Brain rhythms can be divided in high (between 13 and 100 Hz) and low frequencies (between 1 and 13 Hz). Sleep correlates with low frequencies, whereas sensorimotor and mental activities during wakefulness make use of all, low and high frequency domains. The work of Prof. Llinas, at New York University, has greatly contributed, over the last 30 years, to these neurophysiological developments.
The thalamocortical dysrhythmia as common disease mechanism
The term thalamocortical dysrhythmia (TCD) was coined by Prof. Rodolfo Llinas and describes the basic physiological mechanism of functional brain disorders. The developments in this field were primarily conditioned by: 1) the discovery by Llinas and co-workers of the low threshold calcium spike bursts in the early 80’s, 2) the studies performed by them since the 90’s on the normal physiology of the thalamocortical network, and 3) the joining of efforts of this group and of the team of Prof. Jeanmonod since 1998. This close and fruitful collaboration goes on until today, and Prof. Jeanmonod considers Rodolfo Llinas as his neurophysiological mentor and dearest friend. TCD consists in the overproduction of low (1-13 Hz) and high (13-100 Hz) frequency activities between thalamus and cortex, which have been examined in last years thanks to microelectrode single cell recordings in the thalamus during interventions, and are recorded today using non-invasive quantitative electroencephalography (EEG) and magnetoencephalography (MEG). We use a 64 channel EEG recording system with algorithms for spectral power and source localization.
The TCD represents the common basic mechanism at the source of the most different clinical manifestations found in neurogenic pain and tinnitus, movement and neuropsychiatric disorders as well as epilepsy. As in the image of the orchestra, the conductor (the thalamus) is at the source of a basic distortion, which induces the orchestra to overplay in one affected sector. This mechanism is common to all disorders, and the different clinical manifestations correlate with the triggering of the TCD process in corresponding thalamocortical sectors, which sustain either motor, sensory, or mental functions. For example, neurogenic pain can be explained as the result of an overactivity in the pain sector, tremor as the result of the same overactivity in the motor sector.
The TCD mechanism can be described in some details as a chain reaction, as follows:
- A causal anomaly, e.g. amputation, produces a desactivation of pain-related thalamic cells, which causes them to increase their low frequency discharges. In Parkinson’s disease, thalamic cells are overinhibited, which for them is exactly the same as being desactivated (cell membrane hyperpolarization).
- The tight coupling between thalamus and cortex causes cortical areas to overshoot on low frequencies.
- An increase of this tendency develops in various areas of the brain hemisphere through the mechanism of coherence. This correlates with the appearance of negative symptoms, e.g. akinesia (lack of movement), cognitive deficits, reduced body sensation, or reduced hearing.
- The low frequency overproduction causes an increase of high frequency activity, which is at the source of the appearance of the different positive symptoms, e.g. tremor, pain, tinnitus, hallucination and epileptic fit.
Retuning and sparing interventional strategy
When the TCD becomes chronic, severe and therapy-resistant and the clinical and EEG diagnosis is clear, an intervention may be considered. We have developed over the last 20 years a retuning and sparing, minimally up to non-invasive interventional strategy. This one is based fully on the pathophysiological mechanism described here (see Brain Storm) and thus centered on the necessity to reduce/normalize the overproduction of thalamocortical low and high frequencies without reduction of functional thalamocortical loops. In accordance with this goal, we could reactualize/refine already known targets and in addition develop and apply new ones. They can be globally described as selective retuning miniablations (SRMA). These millimeter-large ablations target dysfunctional, i.e. TCD-promoting, modulators in and around the thalamus, which in the process have lost their normal functions. An ablation in such an area, which leaves intact all remaining thalamocortical executors and all functional thalamocortical modulators, provides symptom relief and brings no deficit with it, reducing the TCD without risk for postoperative symptom increase. This is obtained by either a reduction of the low frequency overshoot, or by a reduction of thalamic overinhibition.
Over the last 20 years, a detailed analysis of postoperative results of more than 1000 targets could confirm that this interventional strategy is indeed efficient but also sparing for sensory, motor and mental functions.
The psycho-emotional dimension
The thalamocortical dysrhythmic (TCD) concept allows, and the clinical context demands, an in-depth integration of the psycho-emotional (or ideo-affective) dimension into the therapeutic process. The activation and optimization of self-healing mechanisms is directly related to this.
There is clear evidence for the existence of two sources for the TCD process, that is 1) an anomaly in body or brain, and 2) intense and on-going mental activities, that is ideas and representations as well as their associated feelings. These can be activated by the presence of a chronic disease state and related suffering, but also by personal biographic factors and personality/character traits. Our experience indicates clearly that surgery can provide control of the disease- and emotion-related TCD, and brings in addition, indirectly and logically, a mental improvement due to the obtained symptom reduction. These therapeutic effects can however not take place if a counterproductive mental dynamics contributes to the suffering and has not yet been addressed and solved by adapted psychotherapeutic measures. This is most probably explained by the widespread and bilateral distribution of the thalamocortical paralimbic/associative network that is responsible for mental functions (in short called here the ”emotional brain”), as well as by its extensive interconnectivity with the other, sensory and motor, sectors. This provides the emotional brain with an outspoken, potentially dominant, strength. In other words: the mind of the patient is stronger than the intervention and the surgeon. This is surely an essential observation, which supports fully our integrative therapeutic approach. This one couples intervention and psychotherapy to cover both the somatic, or body-related, and mental dimensions, respectively. This discussion addresses also the important observation, often not considered in our materialistic and linear medical cultural context, that a human being may suffer from intense neurological symptoms originating from both sources, somatic and/or mental. This clearly points to the necessity of an integration of both therapeutic dimensions.
The experimental evidence arises in recent times that mental, especially emotional activity can lead in the brain not only to a TCD but also to cell losses through different mechanisms. This strength of emotions has been demonstrated since years in impressive ways in different ethnological studies, showing that a belief can lead to body damages and even death. This points to a big responsibility toward our brain: our ideas, representations and beliefs can activate damaging processes. We can however also trigger and favour beliefs and emotions which lead to brain health and an activation of our strongly underestimated self-healing possibilities.
Psychoemotional Considerations and Advice for the postoperative phase
After the intervention, disease mechanisms are reduced or controlled. An increase of destabilizing emotional phenomena comprising anxiety, sadness, despair and frustration may nevertheless happen. These may limit symptom relief and cause the appearance of different so-called psychogenic symptoms. These can be recognized by a detailed clinical, psychological and EEG analysis. The following psychodynamic factors may explain the paradoxical appearance of such negative phenomena after the treatment, in the context of the TCD mechanisms described above:
- The expectation of an improvement causes emotional tension, particularly when the symptom relief has been wished for intensively and for long time, and when there is a strong wish for the rekindling of different activities and capacities.
- A fear of symptom recurrence may develop during the first postoperative days in parallel with the joy about obtained improvements.
- The symptom relief liberates the mind, which can now get busy with, and disturbed by unresolved biographic issues and themes.
- The new symptom-free situation submerges the patients with fear due to loss of the long standing disease-related references.
- There rises a frustration activated by the time loss and the limitations brought by the disease.
- After years of chronic suffering, months up to years may be necessary till an emotional stability can be fully reinstated.
An intervention corresponds to an external aid: the patient does not need to perform (with the exception of the trust given to the operative team). A switch toward the mobilisation of internal, self-healing capacities should happen at best immediately after the intervention. Chronic suffering brings regularly a reduction of self-esteem and self-confidence, which may be the roots of depressive developments. These will be important themes for an adapted psychotherapeutic support, as well as reduction of fear, anger, the processing of traumatic events, the integration of the new situation and the modulation of future goals. The psychotherapeutic support serves to mobilize mental capacities toward emotional restabilisation. In our experience, the following factors are of particular relevance:
- The capacity to observe, particularly own concepts and emotions
- The acceptation of the past, of the personal situation and of the impermanence of all things (letting go)
- To take own responsibility for events to come, but without guilt or self-insufficiency feelings
- Trust, patience, self-confidence and “Ur- and Grundvertrauen”
- Mental adaptability, letting go of rigid representations
- Concentration on the “here and now”, away from past dramas and future scenarios
- Seeing the self as multiple, with strengths and weaknesses, positive and negative emotions (e.g. fear and frustration but also trust and courage)
- The search for the “golden middle way”, away from black/white and horror/paradise scenarios
High-tech activities are perfectly compatible with psychological and holistic approaches. Relevant prerequisites for an efficient team activity around the patient are a sufficient amount of integration of their own emotions by team members, empathy as well as trust in the patient’s self-healing abilities. We have collected along the years most positive experiences with such an approach, which seems to be particularly adapted to, and required by our patients suffering from chronic functional brain disorders. We could observe impressive symptom reductions after a few months of psychotherapy. These experiences as well as the existence of a common mechanism for both disease and mental phenomena, namely brain rhythms, lead us to the conclusion that our integrative therapeutic approach has solid ground and stems neither from an a priori nor from fashion.
Operation without incision using focused ultrasound
The world première-project “High energy transcranial MR-guided focused ultrasound (TcMRgFUS) therapy in functional neurosurgery” was developed in close collaboration with InSightec, Ltd and was supported by the Swiss National Research Foundation (NCCR CO-ME), the University of Zürich, the ETH Zürich and the University Children’s Hospital Zürich. It was lead by Prof. Jeanmonod in collaboration with the MR-Center of the University Children’s hospital (Prof. E. Martin), began in September 2008, ended in June 2009, and demonstrated the feasibility, reproducibility, safety, precision and efficiency of the TcMRgFUS. The second study was supported by InSightec Ltd, Rodiag AG, Privatklinik Obach and GE Healthcare Switzerland. It took place between April 2011 and December 2012 in the Center for Ultrasound Functional Neurosurgery in Solothurn and demonstrated a 0.5 mm mean targeting acuracy of the ExAblate Neuro TcMRgFUS brain system. Patients with Neuropathic pain, Parkinson’s disease and essential tremor were treated without complications.
TcMRgFUS allows to ablate with heating, with a millimeter precision, any chosen target area in and around the thalamus without skin incision nor skull opening. This allows a suppression of all risks related to skull and brain penetration. Focused means that 1024 ultrasound waves, each of them innocuous for brain tissue, converge in the target, where sonic energy gets transformed in thermal energy in an area of only 3-4 mm diameter with sharp borders. The desired temperatures are between 53 and 60 degrees Celsius, and the obtained target temperature increase is checked every 3-4 seconds thanks to MR-thermometry. This allows a most important, continuous control of the realized work in the target, and forbids the production of an unseen and undesired thermal increase beyond the target. This procedure provides the patient with an optimization of precision and safety. Data have pointed to the necessity of maintaining the temperature rise below 60 degrees Celsius. This allows to reduce effects on small vessels in the target, providing an optimal bleeding risk reduction.
The procedure is performed without general anesthesia and consists of the fixation of a ring around the patient’s head under local anesthesia, the installation in the MR machine, calibration and targeting pre-treatment MR series, and finally the therapeutic application of focused ultrasound, in close contact with and under supervision of the clinician.
Central Lateral Nucleus (CL)
Medial thalamic nucleus, part of the intralaminar nuclei. It is composed of an elongated, relatively thin portion separating the mediodorsal nucleus (MD) from the ventral tier nuclei, and of an enlarged, mediolaterally oriented posterior portion separating MD from the medial pulvinar. It has diffuse projections to large areas of the neo- and mesocortex and to the striatum.
Electro- Encephalogram (EEG)
Synchronized extracellular currents in a few square cm of cortex generate electrical potentials measurable with electrodes on the scalp. The signal is low-pass filtered to 50 Hz.
Local Field Potential (LFP)
Synchronized extracellular currents of a few hundred cells generate a LFP which reflects the average input to individual neurons. The LFP can be recorded with a microelectrode with impedance up to 0.5 MOhm. The signal is analysed for frequencies up to 100 Hz.
Low-Threshold Calcium Spike (LTS) Bursts
Bursting discharges produced by thalamic and reticular cells, when their membranes are hyperpolarized by either disfacilitation or overinhibition. They are due to the deinactivation of calcium T-channels causing the appearance of a large calcium spike, itself inducing a burst of sodium action potentials.
Magneto- Encephalogram (MEG)
Synchronized extracellular currents in a few square cm of cortex generate magnetic fields measurable with sensors on the surface of the scalp. MEG offers the advantage over EEG that large numbers of sensors are swiftly mounted around the head.
Stereotactic operations performed since the beginning of the fifties against chronic pain. They have been used against both chronic nociceptive and neurogenic pain syndromes, and several different targets within the medial tier of the thalamus have been explored, for example the centre médian-parafascicular complex, central lateral nucleus, posterior complex and medial pulvinar. The results of these operations have been characterized by pain relief without production of somatosensory deficits and without risk for postoperative pain increase. The medial thalamotomy presented in this essay is a central lateral thalamotomy, targeting the posterior part of the central lateral nucleus, where units discharging low-threshold calcium spike bursts were concentrated.
A pain syndrome arising after damage to the somatosensory pathways, from peripheral nerves and dorsal roots (peripheral neurogenic pain) to the spinal cord, brainstem, thalamus and cortex as well as the fibers inbetween (central neurogenic pain). The denominations deafferentation pain, dysesthetic pain, neuropathic pain (for peripheral type) and central pain are also used. Neurogenic pain is characterized by the following clinical descriptors: 1) pain localization in and around the deafferented body part, 2) pain qualities (pins and needles, electrical discharges, burning, tearing and compressive), and 3) timing of the pain: continuous, intermittent in attacks (lasting a fraction to a few seconds) or in episodes lasting more than a minute. The history and the neurological examination often reveal the evidence and signs of somatosensory damage (hypoesthesia and hypoalgesia). The examination may however be normal in some patients if the deficits have been compensated along time. Neurogenic pain responds specifically to antiepileptics and antidepressants, and represents the most frequent indication for pain surgery in case of chronicity and resistance to non-invasive therapies.
Single Unit Activity (SUA)
A microelectrode in the extracellular space records action potentials which constitute the output signal of neurons. The active zone of a tungsten microelectrode has a length of a few microns tapered to a tip of < 1 micron, giving an impedance around 0.5 MOhm. The signal is filtered from 300 Hz to 3000 Hz. On the basis of their size and shape, the action potentials are assigned to individual putative neurons.
Thalamocortical Dysrhythmia (TCD)
Pathophysiological chain reaction at the origin of neurogenic pain. It consists of 1) a reduction of excitatory inputs onto thalamic cells, which results in cell membrane hyperpolarization, 2) the production of low-threshold calcium spike bursts by deinactivation of calcium T-channels, discharging at low (theta) frequency, 3) a progressive increase of the number of thalamocortical modules discharging at theta frequency, and 4) a cortical high frequency activation through asymmetric corticocortical inhibition. These events have been documented by thalamic and cortical recordings in patients suffering from peripheral and central neurogenic pain.
Anatomofunctional entity comprising thalamic cells and their cortical partners, interconnected by thalamocortical and corticothalamic projections and sustaining perceptual, motor and cognitive hemispheric functions. The thalamocortical loop is accompanied by a shorter thalamoreticulothalamic loop. Every module may be subdivided in a specific, or content subpart, providing the substrate for the integration of a given function, and a non-specific, or context subpart, dealing with the interactions between functional domains.
Frequency domain of oscillatory hemispheric activity between 4 and 8 Hz. It has been associated with different functional brain states, e.g. somnolence, cognitive activations, altered states of consciousness like meditation, and, relevant here, dysfunctional brain states like neurogenic pain and tinnitus, abnormal movements, epilepsy and neuropsychiatric disorders (see thalamocortical dysrhythmia).
Ventral Posterior (VP) Complex
Group of nuclei in the ventral tier of the thalamus, receiving the different somatosensory afferents from the whole body. The complex is organized in a topological way, the head being placed medially (ventral posterior medial nucleus) and the foot laterally close to the internal capsule (ventral posterior lateral nucleus). Nociceptive cells have been found in the different parts of the complex, but more specifically in the ventral posterior inferior nucleus, where a pain homunculus was described. The complex projects mainly to cortical areas SI, SII and the insula.