Editing Deep brain stimulation (section)

== Mechanism ==
[[Image:Basal ganglia circuits.svg|thumb|260px|Basal ganglia pathology includes oversynchronization, irregular and rhythmic neuronal discharge, and loss of response selectivity to peripheral stimulation.]]

The exact mechanism of action of DBS is not completely understood.<ref>{{cite journal | vauthors = Moro E, Lang AE | title = Criteria for deep-brain stimulation in Parkinson's disease: review and analysis | journal = Expert Review of Neurotherapeutics | volume = 6 | issue = 11 | pages = 1695–1705 | date = November 2006 | pmid = 17144783 | doi = 10.1586/14737175.6.11.1695 | s2cid = 20857769 }}</ref> The overlapping effects of anatomically distinct targets suggest that either there are as many different DBS mechanisms as there are effective targets or there is some common mechanism that is not unique to any particular target. This has led to viewing DBS from a ''systems'' perspective of circuit modulation rather than focusing only on its local effects.<ref name="Neurosci review 2008"/>

Clinical effects of DBS and lesioning are similar, which led to the initial hypothesis that DBS inhibited local neurons through deafferentation.  Further investigations suggest its mechanism as more complex than simple inhibition of nuclei. For example, activity is increased in the downstream nuclei during stimulation. The apparent paradox of simultaneous cell body inhibition and axonal activation was explained in part by computational modeling studies demonstrating that under extracellular electrical stimulation, the action potential initiates in the axon. Not only does stimulation serve as an on–off switch for modulating circuit oscillations, but that it also induces synaptic reorganization and alters gene expression.<ref>{{cite journal |last1=Sharma |first1=VD |last2=Patel |first2=M |last3=Miocinovic |first3=S |title=Surgical Treatment of Parkinson's Disease: Devices and Lesion Approaches. |journal=Neurotherapeutics |date=October 2020 |volume=17 |issue=4 |pages=1525–1538 |doi=10.1007/s13311-020-00939-x |pmid=33118132|pmc=7851282 }}</ref>

Other studies have suggested that its benefit occurs through modulation of subcellular compartment processes (for example, the [[cell (biology)|cell]] body versus its [[axon]]) and to change in quality depending on time scale (milliseconds, seconds, days, weeks and months). Applying current to neural elements either activates or inhibits of the surrounding elements. The inhibition of neuronal activity may be secondary to depolarization, neurotransmitter depletion, hyperpolarization, or activation of inhibitory afferent projections.<ref name="Lozano 2017"/> Adjusting the frequency in DBS may also change neuronal discharge threshold, altering the relative population of neurons sending out action potentials.<ref name="Vanderbilt 2017"/>

Mechanistic hypotheses include the following:<ref>{{cite book |author1=Mogilner A.Y. |author2=Benabid A.L. |author3=Rezai A.R. |chapter=Chronic Therapeutic Brain Stimulation: History, Current Clinical Indications, and Future Prospects |editor1=Markov, Marko |editor2=Paul J. Rosch |title=Bioelectromagnetic medicine |publisher=Marcel Dekker |location=New York |year=2004 |pages=133–151 |isbn=978-0-8247-4700-8 }}</ref><ref>{{cite journal | vauthors = McIntyre CC, Thakor NV | title = Uncovering the mechanisms of deep brain stimulation for Parkinson's disease through functional imaging, neural recording, and neural modeling | journal = Critical Reviews in Biomedical Engineering | volume = 30 | issue = 4–6 | pages = 249–281 | year = 2002 | pmid = 12739751 | doi = 10.1615/critrevbiomedeng.v30.i456.20 }}</ref><ref>{{cite journal | vauthors = Herrington TM, Cheng JJ, Eskandar EN | title = Mechanisms of deep brain stimulation | journal = Journal of Neurophysiology | volume = 115 | issue = 1 | pages = 19–38 | date = January 2016 | pmid = 26510756 | pmc = 4760496 | doi = 10.1152/jn.00281.2015 }}</ref>
# Depolarization blockade: Electrical currents block the neuronal output at or near the electrode site.
# Synaptic inhibition: This causes an indirect regulation of the neuronal output by activating axon terminals with synaptic connections to neurons near the stimulating electrode.
# Desynchronization of abnormal oscillatory activity of neurons
#[[Antidromic]] activation either activating/blockading distant neurons or blockading slow axons.<ref>{{cite journal |last1=Li |first1=Q |last2=Qian |first2=ZM|title=Cortical effects of deep brain stimulation: implications for pathogenesis and treatment of Parkinson disease. |journal=JAMA Neurology |date=January 2014 |volume=71 |issue=1 |pages=100–3 |doi=10.1001/jamaneurol.2013.4221 |pmid=24189904}}</ref> The orthodromic vector is the typical direction of an [[action potential]] propagation away from the [[neuron]] cell body (soma) towards the [[axon]] terminal; its opposite is antidromic.<ref name = "Embo 2019"/>  Antidromic activation of deep brain nuclei results in orthodromic activation of cortical neurons.<ref name ="Neurosci review 2008">{{cite journal |last1=Montgomery EB |first1=Jr |last2=Gale |first2=JT |title=Mechanisms of action of deep brain stimulation(DBS) . |journal=Neuroscience and Biobehavioral Reviews |date=2008 |volume=32 |issue=3 |pages=388–407 |doi=10.1016/j.neubiorev.2007.06.003 |pmid=17706780}}</ref>

Electrophysiological studies showed that cortico-basal circuits in chronic neurologic disease are [[Tonic (physiology)|tonically overactive]] with [[synchronization|oversynchronization]], irregular and rhythmic neuronal discharge, and loss of selectivity in response to peripheral sensitive stimulation.<ref name="Lancet Neurol 2014"/>

Phase amplitude coupling is a measure of how the amplitude of an oscillation in a given frequency band correlates with the phase of another frequency band, a normal process that occurs with functions such as memory, learning, and cognition. In Parkinson's there is an excessive beta-gamma coupling, which, when suppressed by DBS, correlates in magnitude to the degree of clinical improvement.<ref name = "Handbook Clinical Neurology 2022"/>

There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions, for example, its roles in movement or learning. Instead, it appears that high-frequency DBS mitigates abnormal basal ganglia output into a more tolerable pattern, helping to restore downstream network function. In support of this theory is the observation that in a normal healthy brain, all basal ganglia connections are inhibitory except for those from the STN.<ref name="Neurotherapeutics 2016">{{cite journal |last1=Wichmann |first1=T |last2=DeLong |first2=MR |title=Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality? |journal=Neurotherapeutics |date=April 2016 |volume=13 |issue=2 |pages=264–83 |doi=10.1007/s13311-016-0426-6 |pmid=26956115|pmc=4824026 }}</ref>

The STN, the most common nucleus targeted in Parkinson's, integrates motor, cognitive, and emotional information to orchestrate complex behaviors. Furthermore, fMRI studies showed that the STN is involved in emotional processes such as amusement, disgust, sexual arousal, and maternal and romantic love. On fMRI STN-DBS reversed the hypometabolism in motor, associative, and limbic prefrontal areas observed in Parkinson's disease and the diffuse hypermetabolism of the prefrontal cortex.  The functional deafferentation of the STN induced by DBS seems to improve executive functions, but reduction of reaction time hastens the decision, which could lead to impulsive and erroneous choices.<ref name="Lancet Neurol 2014"/>

[[Image:Basal ganglia diagram.svg|thumb|260px|DBS disrupts pathologically elevated positive and negative feedback loops in the motor pathway via basal ganglia deafferentation]]

Histopathologically, the brain parenchyma surrounding the leads develops [[glial scar|gliosis]] over time, and occasionally a [[microglia]]l infiltrate.<ref>{{cite journal |last1=Vivanco-Suarez |first1=J |last2=Woodiwiss |first2=T |last3=Fiock |first3=KL |last4=Hefti |first4=MM |last5=Uc |first5=EY |last6=Narayanan |first6=NS |last7=Greenlee |first7=JDW |title=Neurohistopathological findings of the brain parenchyma after long-term deep brain stimulation: Case series and systematic literature review. |journal=Parkinsonism & Related Disorders |date=16 December 2024 |volume=133 |page=107243 |doi=10.1016/j.parkreldis.2024.107243 |pmid=39721929}}</ref>

When therapeutic target sites are near areas causing adverse effects, monopolar stimulation, in which the brain is the cathode and the neurostimulator the anode, can be modified to bipolar in which another electrode serves as the anode rather than the neurostimulator, yielding a narrower area of stimulation.<ref name = "JAMA neurology 2013"/>

The coordinated reset counteract pathological synchronization processes by providing an [[Kindling model of epilepsy|antikindling]] effect and retraining the neural network.<ref name = "JAMA neurology 2013"/>

Either there are as many different DBS mechanisms as there are effective targets or there is some common mechanism that is not unique to any particular target. This suggests that it may be profitable to view DBS from a systems perspective rather than just its local effects, an approach that here-to-fore has not been received much consideration.<ref name ="Neurosci review 2008"/>

The electrical effects of clinically applied DBS are strongly influenced by the [[anisotropic]] nature of the tissue at the target site in relation to the electrode and can therefore cause heterogeneous electrophysiological, structural, molecular, and cellular reactions. DBS seems to uncouple STN neurons from its axons and cause a functional deafferentation from both efferent and afferent structures.<ref name = "Embo 2019"/>