Damian Sendler: Although early data suggests that deep brain stimulation (DBS) is clinically effective, it has been challenging to develop into a solid treatment. In part, this is due to a lack of understanding of its mechanics. We look at how DBS affects brain networks in mobility and mental disease investigations. From this, we conclude that future DBS investigations should use a network-oriented approach. Identifying patients with particular circuit/network abnormalities is an essential part of the network approach. Using dimensional diagnostic techniques, we show how an accurate diagnosis may be made more quickly. Finally, we’ll talk about creating self-adjusting “closed loop” systems using network/circuit biomarkers.
Damian Jacob Sendler: When it comes to OCD and depression, deep brain stimulation (DBS) seems to be a promising treatment option, but typical randomized studies haven’t been as successful. DBS has been successful in Parkinson’s disease (PD) and is now considered standard treatment2. People with Parkinson’s disease and other movement disorders suffer from symptoms that can be reliably measured by brain circuitry that has been extensively studied. Not all of the brain circuits that contribute to mental illness are recognized or well-understood3,4. Our symptom assessments are also less reliable, which reduces the strength of the clinical signal5,6. Depression surveys demonstrate that general characteristics like mood account for more variation than any single symptom of MDD7, for instance. There was more comorbidity than “pure” disorders in the DSM-5 field trials, which suggests that diagnostic criteria and rating scales don’t measure distinct entities 8.
Dr. Sendler: DBS has been studied in psychiatric and Parkinson’s disease patients, and the results have led to novel therapy options. Some of these concepts are focused on anatomy, while others are more utilitarian. At the circuit/network level, we contend that DBS in psychiatry is reliant on both function and anatomy. Functional and network theories of psychiatric DBS are discussed here. Each part begins with a review of what is now known or highly suspected, followed by a discussion of potential future prospects for the discipline.
Damian Sendler
These discrepancies may be explained by DBS’s potential to impede the movement of data Axons and cell bodies are essentially “taken over” by DBS because high-frequency pulses (above 100 Hz) are above the firing frequency of most neurons. The irregularity and variability of normal brain activity provides information. DBS reduces the quantity of information sent between network nodes in a mathematical sense20 by introducing regularized, less-variant activity19. This might improve the overall performance of the network. Neuronal information (or “entropy”) was shown to rise when Parkinsonism appeared in an animal model with half the normal number of parkinsonian neurons (i.e., half the normal quantity of information). The DBS of those areas lowered local information, but boosted the flow of information between these regions21. So far, the informational lesion idea has only been tested in Parkinson’s disease, but the findings were promising. High-frequency DBS was shown to be equally effective as pulse sequences tailored for information blockage in a human study22.
Coordination of activity both inside and across regions is required for neural network communication. Coordinated oscillations in the local field potential (LFP)23 and scalp electroencephalogram (EEG) may be seen when networks are working properly (EEG). Rhythmic DBS may be able to restore normal oscillatory activity in patients with neural network disorders. During movement, for example, beta band (12–30 Hz) power tends to decrease24. It is hypothesized that PD’s basic symptoms of bradykinesia and stiffness are the result of coordinated (i.e., coherent) beta oscillations in the cortico-basal circuits. Subthalamic nucleus and motor cortex cross-frequency coupling was reduced in patients who had DBS for the first time27. As with the strength of gamma band activity nestled inside alpha/beta band activity decreasing in OCD patients after DBS of the ventral striatum/ventral capsule, this result was not replicated in an independent sample29. Identifying oscillatory biomarkers for mental disease is a tough task that we will return to in a moment. One of the most significant outcomes of PD’s beta results was the development of DBS devices that can capture and retain electrophysiologic data from human patients during treatment. An unprecedented picture of brain activity is provided by these systems
A new therapeutic approach may be possible as a result of DBS’ impact on oscillations. As an example, theta in anxiety disorders32 or beta in PD25,33 might be targeted with stimulation that coincides with the phase of frequency of the band of interest. The use of phase-dependent DBS (i.e., DBS administered in sync with beta band activity) was shown to be better than high-frequency, constant DBS in a PD study33. A transcranial magnetic device working on the same frequency-locked principles has shown promising results in the treatment of depression34. New research is being conducted to improve oscillations in the cortico-striatal circuitry of those who suffer from OCD (NCT03184454). Oscillation-based DBS may be effective in treating mental illnesses as we improve our ability to recognize the oscillatory properties of abnormal neural networks.
Long-term learning and rearrangement in the brain are made possible through neuroplasticity35. A delayed shift in symptoms is consistent with neuroplasticity effects17,26,36, suggesting that DBS may function via neuroplasticity in the treatment of psychiatric disorders. Animal studies37–40 provide credence to this theory. It was shown that a single DBS session boosted the performance of stressed rats on a working memory test, but only when assessed 33 days following the DBS session. DBS of the ventromedial prefrontal cortex, a possible rodent analogue of the human subcallosal cingulate, was shown by Chakravarty et al.38 to improve synaptic density in rats. DBS abolished the plasticity in the nucleus accumbens (NAc) that had been produced by cocaine in animals. Only when combined with a D1R antagonist that reduced local excitability was DBS able to inhibit sensitization responses generated by repeated cocaine exposure. These results show that deep brain stimulation (DBS) has the ability to modify neuronal network structure and induce neuroplasticity. An important factor in the treatment of mental illnesses is the impairment of learning and plasticity.
Damian Jacob Sendler
Networks are the focus of modern neuroscience. Psychiatric dysfunctions are usually thought to be neural network dysfunctions, therefore DBS is likely to operate at the network level. Corticobasal ganglia network44 includes the subthalamic nucleus and globus pallidus internus, both of which may be treated with DBS for Parkinson’s disease (PD). Excessive firing in globus pallidus and other downstream consequences are thought to be caused by reduced excitation from the STN to the GPL.45 PD46’s motor signals are reduced as a result of normalizing activity in the cortico-basal loop. OCD neurosurgery targets nodes in the cortico-striato-thalamo-cortical10,47,48 circuits, which are related with OCD. Using contemporary imaging techniques, like as diffusion tensor imaging (DTI) and functional connectivity MRI, researchers may better understand structural and functional networks. DBS processes may now be studied in more detail at the network level thanks to this.
DBS has network effects that may be seen in areas that are in close proximity to a DBS target. CBF to the subgenual anterior cingulate (Cg25) and the surrounding orbitofrontal cortex was shown to be lowered following DBS in a research by Mayberg and colleagues13. There were also CBF alterations in other depression-related areas such as the dorsolateral prefrontal cortex and the hypothalamus in long-term DBS responders.
Acute stimulation produces the same results. Acute high-frequency (clinically effective) DBS enhanced CBF in the right medial orbitofrontal cortex (OFC) and right dorsolateral putamen, according to the research of Rauch et al. For the same reason, Dougherty and colleagues47 found higher regional CBF in OCD patients’ dorsal anterior cingulate cortex (dACC) when the stimulation DBS contact was located more ventrally in the VC/VS. The improvement in the intensity of OCD patients’ depressed symptoms was likewise connected with this impact. When greater dorsal stimulation was used to activate the network, rCBF levels increased in the thalamus, striatum and globus pallidus, respectively. These findings show that DBS has to affect a broad range of networks in order to be clinically beneficial. Recent DTI studies51,52 corroborate the wide-network concept. For instance, Riva-Posse et al. recently discovered four white matter bundles in a group of DBS responders51 that were uniquely engaged. DBS was subsequently employed to target the discovered bundles in a fresh group of MDD sufferers by researchers. It was shown that the new prospective (although unblinded) group had response rates of 73% at six months and 82% at one year, substantially greater than those in a previous non-targeted DBS trial54.
Damian Jacob Markiewicz Sendler: Network-oriented DBS is also informed by optogenetics, which uses light to modulate neuronal activity55. DBS processes can be narrowed down to particular sub-networks in animal models via optogenetic activation of specific connections between brain nuclei. Gradinaru et al.56 recently examined whether the impact of DBS in PD is due to suppression of STN or to a disruption in connection between STN and motor cortex. In hemiparkinsonian rats, specific inhibition of STN did not alleviate PD symptoms, according to the researchers. Optogenetic stimulation of the STN-projecting afferent motor cortex neurons was the sole way to alleviate the symptoms of Parkinson’s disease. Indeed, optogenetic activation of certain projections has profound impacts on a range of laboratory behaviors that simulate features of mental illness57. Similar research should be achievable in animal models of mental disease.
DBS’ therapeutic benefits may be influenced by alterations in brain physiology, such as changes in information flow, oscillatory synchronization, and synaptic weighting. Rather than acting on a single brain structure, each of them seems to have a network-level effect. Physiological changes may be caused by a variety of DBS procedures and/or combinations of DBS and targeted pharmacotherapy, as mentioned above. To monitor these changes and modify stimulation strength without immediate physician participation, new closed-loop technologies will soon be available. A formidable toolkit, its primary drawback is that we don’t know which physiologic alterations may be therapeutic for particular mental disease. Finding physiological biomarkers, particularly in MDD60, has been extensively studied in the literature. Our group’s efforts to independently reproduce potential markers have failed61–63. The findings are highly varied. We believe that this issue stems from the wide range of category psychiatric diagnoses64. One neuronal deficit is not enough to explain the phenotypes of depression, obsessive-compulsive disorder, and other DBS-targetable illnesses. The Research Domain Criteria (RDoC) effort of the National Institute of Mental Health aims to recast mental diseases as statistically characterized impairment in distinct functional domains4,6 rather than diagnoses. Mental health disorders may benefit from this domain and circuit-based approach. DBS activates particular circuits, which may cause to behavioral alterations that are distinct from those seen in standard diagnosis. 64 Cross-diagnostic network signatures are presently being identified in psychiatric populations by several research teams65,66, and stimulation based on these signatures may affect psychiatrically relevant behaviors as recently as this past year.
DBS, as currently conducted, is a “open loop” procedure. To put it another way, a single pattern of stimulation is administered to the patient’s brain over a period of many weeks to months9, taking into consideration clinical data. Physicians’ subjective judgments as well as indirect behavioral assessments are used to make choices in this technique, which is heavily trial and error oriented. 4–6. Closed loop DBS is a new option. Neuronal biomarkers, such as enhanced beta band activity in the STN in PD24,25, may be discovered using this paradigm. A direct measurement of the biomarker may then be used to modify stimulation settings. Medtronic’s PC+S DBS system can capture LFP from lead contacts at the stimulation site30, which is a feature available in contemporary DBS systems. These prediction algorithms may help to alter stimulation settings such that the desired neurophysiologic signature is achieved. Early studies have shown that this method can match or even outperform standard DBS in certain cases44,68.
It is the goal of DBS to modify emotional brain function to enhance results in psychiatric treatment. Patients’ autonomy, decision-making ability, subject selection, control over the device’s operation, and informed consent are among the issues raised by this DBS impact. It is possible that DBS may affect a patient’s sense of authenticity, generate a feeling of estrangement from that “genuine self,” or modify interpersonal dynamics75. Patients with MDD and OCD who had had DBS surgery were studied by Klein et al76, for example. DBS has helped some patients recover to their “true self,” notwithstanding the difficulty in determining how much of their emotional condition was due to the treatment. The clinical experience of DBS is not restricted to psychopathological symptoms, according to de Haan et al.78, in agreement with those findings. Participants’ feeling of self-reliance and fundamental trust are infused with it. Because of the peculiar character of DBS, the authors proposed that individuals have the option of contacting other DBS participants. Subjects’ inability to make informed judgments is another problem with DBS consent. According to Fisher et al.79, TRD patients with intact decisional capability were observed to have a therapeutic misconception—the inability to distinguish between therapy and clinical research. In order to fix this problem, participants should be educated by people who are not directly engaged in the research. Advanced technologies, especially those with some ability to self-adjust, will make these issues increasingly relevant. Ethical review and/or research ethicists will likely be included directly into the design of future DBS trials.
Damien Sendler: DBS is expected to have a network-level impact based on the experimental findings mentioned above13,16,56,67. Information transfer between brain structures21, disruption of pathological oscillations27, and long-term plasticity37,38,40 are some of the possible processes. The phenomena of inter-neuronal communication encompasses all of these systems in one way or another. As a result, viewing DBS through the lens of a network treatment may provide light on its effects and applications59.
Patients may not be able to effectively modify networks by manual DBS parameter programming. Movement disorders have shown early success for closed-loop DBS technology, which employs neural signal-based algorithms to dynamically alter therapy settings. There are also mental disease pilot closed-loop investigations59. When it comes to psychiatry, a method that takes into account several dimensions may assist determine which individuals are most likely to benefit from DBS at a certain target location. This novel, but as yet unproven, treatment has great therapeutic potential if its mechanics and underlying principles can be better understood.
