Peter R. Martin: Historical Vocabulary of Addiction, Vol. II

Neuromodulation

According to the electronic version of the Oxford English Dictionary (OED) the noun neuromodulation is an amalgamation of the combining form neuro- with the noun modulation.  The combining form neuro- (used for: “Forming scientific terms with the sense ‘of or relating to nerves or the nervous system’”) is aborrowing from Greek νευρο-, νεῦρον — in ancient Greek, νευρο- is a combining form of νεῦρον (sinew, tendon, nerve, cognate with nervus, which is the noun nerve in classical Latin). 

The noun modulation is of multiple origins, partly a borrowing from French modulation which, in turn, is derived from classic Latin modulātiōn-, modulātiō (according to OED meaning, “inflection of tone, calculation of measurements from a standard unit [in architecture], also in post-classical Latin in senses ‘melody’..., ‘singing, making music’”).  Additionally, the noun modulation is a combination of modulāt-, past participial stem of modulārī (“to regulate [sounds] in accordance with the rules of melody, pitch, etc., to set to music, to make music, to measure”) and the suffix ‑iōn (“Forming nouns of action from verbs”).

The earliest known use of the noun modulation is in Middle English in a quotation translated from Latin around 1398 by the Cornish writer and translator John Trevisa (flourished during 1342 – 1402 AD) from De Proprietatibus Rerum  (“On the Properties of Things”) originally written by Bartholomaeus Anglicus (before 1203–1272), an early 13th-century Scholastic of Paris and member of the Franciscan order (Bartholomaeus, Trevisa and Seymour 1975):  “Simphonia is temperate modulacioun [Latin modulationis] acording in sownes hiȝ and lowȝ.” The now obsolete meaning of modulation as used in this quotation is defined in OED as: “The action of singing or making music; a tune, a melody; (in plural) musical notes or sounds.” 

Of the many meanings of the word modulation listed in OED, the most relevant with respect to formation of neuromodulation, the subject of this discussion, are those used in Physics and Engineering and in Biology.  The first use in English of modulation as applied to the physical sciences appeared in the journal Science (Stebbins 1919): “One hundred and forty dollars to Professor E. M. Terry... for work on the modulation of radio-energy employed in wireless telephony.”  The relevant definition in OED of modulation is: “The process of modulating an electromagnetic wave or other oscillating signal, or a beam, especially in order to impress a signal on it; the extent to which a modulated carrier wave is varied; the modulated waveform or signal itself”

An early use of modulation in English as applied to biology is found in Principles of development: a text in experimental embryology by Paul Alfred Weiss (1898 – 1989), an Austrian biologist who specialized in morphogenesis, development, differentiation and neurobiology (Weiss 1939): “This physiological, strictly nonprogressive fluctuation of a cell in response to its environmental conditions may be called modulation. It provides for a certain latitude within which a cell can comply adequately with certain variable functional demands of the developed body.”  The definition in OED of this meaning is: “Reversible variation in the activity or form of a cell in response to a changing environment; an instance of this.”

The noun neuromodulation first appeared in OED in 2003 and has since become a widely used word in neuroscience, and more recently, in the treatment of a variety of neuropsychiatric disorders.  The definition in OED for neuromodulation is: “a. Modulation of neurotransmission or neural activity, especially by a neuromodulator; b. electrical stimulation of nerves for the treatment of a muscular or neuromuscular [and recently neuropsychiatric] disorder.”  Of note, this definition of neuromodulation has two subdivisions — the first refers to biochemical/pharmacological means of influencing neurotransmission; the second, to electrical/magnetic stimulation used to modify neural activity within the nervous system. 

Precisely when the word neuromodulation was first used in the English language is uncertain.  OED reports that the word appeared in the journal Aggressologie in 1975: “Hormonal regulation in ‘constancy’ and central nerve servo-mechanism in control of operation of the hypophyso-cortico-suprarenal couple.  Part played by neuromodulation and environment.”  Although reference to this quotation in OED is incomplete, there is, indeed, an article with an almost identical title in the same journal/volume — but in French — by Henri Laborit (1914 – 1995), the French surgeon, neurobiologist and philosopher who was instrumental in the development of the drug chlorpromazine in mid-20th century that changed psychiatric practice forever.  The quotation refers to neuromodulation of a part, or axis, of the body’s endocrine system. Within the hypothalamic-pituitary-adrenal axis, at each level, activation of release of the appropriate hormone occurs in response to stressors that may originate from the mind/body and/or from environmental demands. These hormones, in addition to their physiological effects throughout the body, actuate negative feedback loops resulting in inhibition of the release of these same hormones.   Thus, stability within the body system is maintained while adapting to the demands of the environment (termed homeostasis) (Martin 2024).

Another form of neuromodulation is referred to in a quotation of Martin Rodbell (1925 – 1998), an American biochemist and molecular endocrinologist best known for his discovery of guanine nucleotide-binding (G-) proteins for which he shared the 1994 Nobel Prize (Cooper and Rodbell 1979): “It is possible that this interaction may serve as a model of the means whereby neurotransmitters and adenine nucleotides, which are commonly secreted together in synapses, participate in the ‘neuromodulation’ of physiological events.”  This quote indicates that in addition to the specific neurotransmitters that are secreted by neurons into their synapse (Elson and Selverston 1992), other co-released neuroactive compounds contribute to the resulting neuromodulation of postsynaptic neuronal activity.

Finally, neuromodulation can be bioelectrical in nature — neurostimulation can be performed using an electric current applied or delivered from an external source to nervous tissue in any part of the body in order to initiate, inhibit or adjust neuronal activation (depolarization), as indicated in a quotation from The Journal of Urology (Hasan, Robson, Pridie et al. 1996): “Despite the growing interest in functional electrical stimulation, experience with neuromodulation in patients with proved idiopathic detrusor instability is currently limited.”  Most relevant to our discussion is stimulation of neurons/neuronal circuits in the brain, which can be carried out in a similar manner, but more challenging to accomplish because the brain is encased in a thick boney skull. 

A magnetic field can also induce an electric current — this physical principle was first discovered by the English chemist and physicist Michael Faraday (1791 – 1867) and subsequently proven mathematically by James Clerk Maxwell (1831 – 1879), the Scottish physicist and mathematician responsible for the classical theory of electromagnetic radiation (Maxwell and Thompson 1904).  Accordingly, neuromodulation can also be accomplished by applying a magnetic field to induce an electric current in a region of interest of the brain.

Neurostimulation of the brain began with the historic work of Gustav Fritsch (1838 – 1927), a German anatomist, anthropologist and physiologist and the German neuropsychiatrist Eduard Hitzig (1839 – 1907) who studied the application of electric current to the brain.  In 1870, by electrically probing the cerebral cortex of a dog, they demonstrated that neurostimulation of different areas of the cerebrum caused involuntary contractions of specific muscles and thus for the first time localized the motor areas of the brain (Fritsch and Hitzig 1870).  

An analogous advance of historic proportions related to unravelling the sensory input and processing of pain by the nervous system to produce the associated emotional experience as proposed by the Canadian psychologist Ronald Melzack (1929 – 2019) and the British neuroscientist Patrick David Wall (1925 –2001) known as the gate control theory of pain (Melzack and Wall 1965).   This discovery revolutionized the field of pain management and led to the development of spinal cord stimulation and other forms of neuromodulation (Illis 1983). 

Finally, neuromodulation has been employed in the treatment of neuropsychiatric disorders with the emergence of functional neurosurgery.  Starting in the 1940s with ablative lesions (Penfield, Erickson, Jasper et al. 1941) and slowly transforming to employing electrical stimulation as an alternative to ablative procedures.  Stereotactic techniques allowed for more precise targeting of specific brain regions, leading to modern neuromodulation therapies and deep brain stimulation (DBS) for treatment of movement disorders such as Parkinson's disease and subsequently, a wide range of conditions, including dystonia, epilepsy and psychiatric disorders (Benabid, Chabardes, Seigneuret et al. 2005). 

Although relatively late to the neuroscience nomenclature, neurobiological investigations related to neuromodulationwere the conceptual foundation for many of the most important advances in neuroscience (Martin 2021).  The concept of neuromodulation required exploration of the nervous system as structurally delineated by experimental histologists in the 19th century — leading to an understanding of how neuronal function depends on its structure.  Camillo Golgi (1843 –1926) and Santiago Ramon y Cajal (1852 –1934) provided the underpinnings for our understanding of how the brain was constructed histologically for which they were jointly awarded the Nobel Prize in 1906 (Golgi 1885; Ramon y Cajal 1909). 

Subsequently, Sir Charles Scott Sherrington (1857 –1952) and Edgar Douglas Adrian (1889 – 1977) performed impactful research on the neurophysiological functioning of neurons for which they were co-recipients of the 1932 Nobel Prize.  Sherrington himself coined the word “synapse” to define the connection between two neurons and his major contributions can be found in The Integrative Action of the Nervous System (Sherrington 1906).  His research on the reflex arc and the concept of synaptic transmission laid the groundwork for modern theories of neuromodulation.  Of note, neuromodulation is distinct from conventional neurotransmission, as it involves the alteration of neuronal excitability and synaptic transmission through various mechanisms, including ion channel modulation and neurotransmitter release (Kaczmarek and Levitan 1987).

 Brain stimulation therapies, based conceptually on the fact that the brain is an electrochemical organ, have been relatively late in joining psychopharmacology and psychotherapy among the full-fledged treatment approaches now used in psychiatry (Austelle,  Higgins and George 2025).  Brain stimulation techniques are distinct from the other two forms of psychiatric treatment in that they are targeted to neuroanatomically-specified brain regions demonstrated to be responsible for precise brain functions (Broca 1865; Fritsch and Hitzig 1870; Wernicke 1874; Brodmann 1909; Penfield, Erickson, Jasper et al. 1941).    

Brain regions selected for stimulation are posited to provide entrée to and thus, modulate (excite or inhibit) activation of neural circuits, which, in turn, are organized to form even more complex large-scale brain networks that account for complex mental and neural phenomena and experiences based on our understanding of neuroanatomic and conceptual organization of the functioning brain (Ramon y Cajal 1909; Papez 1937; Hebb 1949; MacLean 1952; Raichle, MacLeod, Snyder et al. 2001; Mayberg 2003). 

Dysfunction(s) of these neuroanatomically and physiologically organized brain areas are postulated to be responsible for expression of psychopathology in neuropsychiatric disorders.  Accordingly, various methods are now being developed in order to allow psychiatrists to remedy abnormal functioning of the brain by directed neurostimulation of relevant brain regions as a part of the clinical management of various neuropsychiatric conditions. 

Neuromodulation approaches for treatment of primary alcohol/drug use disorders and behavioral addiction have become increasingly realistic as the neuroanatomic underpinnings and brain circuitry of these conditions became elucidated (Olds 1958; Naqvi, Rudrauf, Damasio et al. 2007; Koob and Volkow 2010).  An early attempt to treat drug addiction by neuromodulation (although the term was not yet in use) involved electroconvulsive treatment (ECT) — provoking a brief, controlled generalized seizure activated by an electric current applied to the scalp either unilaterally or bilaterally.  ECT was discovered by the Italian neurologist Ugo Cerletti (1877 – 1963) and has been used in psychiatry ever since, especially in treatment of serious psychiatric illnesses (Kalinowsky 1986).  ECT was proposed for study because in this era, addictive disorders were believed to share many of the characteristics of psychotic illnesses — both are characterized by behaviors that are learned, reinforced and dysfunctional (Martin 2019) and also resistant to other then existing treatments (Roper 1966):

“The drug addict, unable to control his addiction despite some apparent awareness of its consequences, shows irrational behaviour, similar to certain aspects of psychotic illness.  This similarity suggested that forms of therapy which can change patterns of psychotic illness might have a similar effect on drug addiction.

“One of the most effective techniques of changing psychotic behaviour is electroconvulsive treatment (ECT).  Recent advances in these techniques... have improved their effectiveness considerably, so that now radical changes of a more or less permanent nature can frequently be achieved.  This is particularly so with intensive ECT…  This treatment was therefore considered for drug addicts in whom other treatment techniques had failed and who, hence, had poor prognoses…

“The good effects of this therapy are perhaps due to its greater ability to bring about radical changes in the patient's behaviour.  If drug addiction is viewed as an example of learned behaviour with continual repeated reinforcement, the good therapeutic results reported here can be looked upon as the interruption of established and self-perpetuating habit patterns.”

Recently implemented neuromodulation approaches for the treatment of addictive disorders involve an electrical current of much lower intensity than ECT, generated either by a magnetic field (transcranial magnetic stimulation, TMS) or direct stimulation with a low intensity current (transcranial electrical stimulation, tES and direct current stimulation, tDCS).  The purpose is not to cause a seizure as with ECT, but instead to specifically target and repeatedly stimulate — at high or low frequency to increase or inhibit cortical excitability, respectively — specific cortical regions associated with neural circuits in brain regions crucial for decision-making, impulse control, and craving (Koob and Volkow 2010; Salling and Martinez 2016).  

Stimulation of these circuits is intended to alter synaptic connectivity via Hebbian forms of synaptic plasticity involving the molecular mechanisms of long-term potentiation and long-term depression (Martin 2021).  These are non-invasive neuromodulation approaches that stimulate the brain from outside the skull.  Accordingly, they have received the greatest research attention as a potential treatment approach for management of addictive disorders, presumably not as a stand-alone treatment modality but as a component of an integrated pharmacopsychosocial strategy (Martin, Weinberg and Bealer et al. 2007; Ward, Blyth and Kast 2025). 

A more invasive method of neuromodulation, deep brain stimulation (DBS) that requires surgical placement of electrodes, is supported by basic research findings beginning from the last century and hence, may also play a role in addiction management (Mehta, Praecht, Ward et al. 2024), despite the difficulties of its integration in a comprehensive addiction treatment program.

Reminiscent of the ground-breaking research on brain self-stimulation by Olds and Milner (1954), the potential for treating cocaine addiction using neuromodulation (DBS) was tested in a rat experimental model by repeated high-frequency stimulation of the brain reward system (Levy, Shabat-Simon, Shalev et al. 2007).  Localized electrodes were used to stimulate the medial forebrain bundle at the lateral hypothalamus (LH) or the prefrontal cortex (PFC) in the animals.  Repeated high-frequency stimulation in either site influenced cocaine, but not sucrose reward-related behaviors in the subjects.  Stimulation of the LH reduced cue-induced seeking behavior, whereas stimulation of the PFC reduced both cocaine-seeking behavior and the motivation for its consumption and were accompanied by glutamate receptor subtype alterations in the nucleus accumbens and the ventral tegmental area (Kalivas and Volkow 2005; Hyman, Malenka and Nestler 2006).   

Feasibility in the clinic of neurostimulation of brain reward pathways (Martin 2023) is suggested by analogous findings from two case reports of the successful treatment of a few patients with alcohol use disorder employing DBS of the nucleus accumbens (Kuhn, Lenartz, Huff et al. 2007; Müller 2009).  The important role of the reward circuits in humans is also supported by the positive clinical outcomes resulting from ablation of the nucleus accumbens by stereotactic surgery, which was reported to alleviate alcohol craving, reduce relapse rates and improve quality-of-life in patients with alcohol use disorder (Wu, Wang, Chang et al. 2010).   Much of this work harkens back to the instructive neurostimulation and ablation studies of various brain regions conducted for surgical treatment of epilepsy at the Montreal Neurological Institute by the American Canadian neurosurgeon Wilder Penfield (1891 – 1976) starting in the 1940s (Benabid, Chabardes, Seigneuret et al. 2005; Murrow 2014). 

When addiction is secondary to, or a consequence of another underlying psychiatric disorder such as depression  (Martin 2016) it seems reasonable to treat the primary disorder with the appropriate neurostimulation/neuromodulation technique because these treatments have been the most extensively investigated, especially ECT, which remains the most effective treatment for this disorder (George, Nahas, Molloy et al. 2000; Mayberg, Lozano, Voon et al. 2005; Lisanby 2007). 

The U.S. Food and Drug Administration (FDA) has approved TMS treatments for psychiatric disorders such as depression and obsessive-compulsive disorder with the proviso that they should be used when other medical treatments fail — meaning that clinical studies have established the effectiveness and the adverse effects of the medical devices employed, showing that a new device is non-inferior to a previously FDA approved medical device.  

As patients with addiction have typically been excluded from neurostimulation treatment studies of depression and other primary psychiatric disorders, it is unclear whether these treatments would be effective, or are indicated for, secondary addiction.  Moreover, it is still controversial whether co-occurring addictive disorders represent positive or negative predictors for ECT treatment outcome in co-occurring depression (Moss and Vaidya 2014; Aksay, Hambsch, Janke et al. 2017), not to mention outcomes for depression treated with newer forms of neurostimulation.  

Despite the scientific interest in neuromodulation and the fact that repetitive transcranial magnetic stimulation (TMS) has recently receive approval from the FDA for short-term smoking cessation (Zangen, Moshe, Martinez et al. 2021; Cohen, Bikson, Badran et al. 2022), these treatments are still considered experimental. Though “promising,” based on several systematic reviews and meta-analyses and this remains a highly active research subject (Gorelick, Zangen and George 2014; Salling and Martinez 2016; Verdejo-Garcia, Lorenzetti, Manning et al. 2019; Mehta, Praecht, Ward et al. 2024). 

Although treatment of substance use disorders have been individually studied, differences in response to neuromodulation by individuals with different substance use disorders may be less important than the behavioral underpinnings that are common to all addictive disorders and associated psychopathology (Madeo and Bonci 2024; Bright, Overstreet, Levey et al. 2025).  At this early stage, neurostimulation studies have focused on substance craving and reward, often determined by brain fMRI activation changes with drug related cues. 

The rationale for development of neuromodulation in the clinic seems most rational for those addictive disorders for which there are no currently established pharmacological treatments — cannabinoids (Kearney-Ramos and Haney 2021) and stimulants (Steele, Maxwell, Ross et al. 2019; Zhai, Salmeron, Gu et al. 2021) and behavioral addictions (Wu, He, Wang et al. 2025) — but most work to date has been with alcohol and nicotine/tobacco (Salling and Martinez 2016).    

At this early stage of research in this domain, neurostimulation techniques/methods employed, the number of stimulation sessions, combination with pharmacotherapy and/or psychotherapy and other important issues of clinical trial design are highly variable and lack the sophistication that have been routinely employed for some time in studies of pharmacological treatments.   Simple variables such as the ideal placement of electrical or magnetic stimulation remain difficult to select and optimize and may vary with drug and or behavioral addictions (Soleimani, Joutsa, Moussawi et al. 2024).  There needs to be improved and consistent clinical trial methodology developed for neurostimulation.

Moreover, the notion of significant added benefits offered by neurostimulation, when added to other elements of a comprehensive pharmacopsychosocial treatment of addictive disorders have yet to be systematically considered (Ward, Blyth and Kast 2025).  There are very few studies (Harel, Perini, Kämpe et al. 2022) that address clinical efficacy of neuromodulation in an analogous fashion to classic pharmacological studies in alcohol (naltrexone and many other agents) and opioid use disorders (methadone, buprenorphine and naltrexone), the results of which resulted in FDA approval and have become part of clinical practice. 

In summary, neuromodulation is a relatively newly formalized treatment modality in neuropsychiatry, but one that should join psychopharmacologic and psychotherapeutic approaches in our armamentarium as the brain is an electrochemical organ.  The rationale behind application of electric and magnetic stimulation (e.g., transcranial magnetic stimulation, transcranial direct current stimulation and deep brain stimulation) in specific brain regions is to reestablish normal brain function in targeted cortical regions associated with the neural circuits crucial for decision-making, impulse control and reward and craving in an effort to dampen addictive behaviors. 

Acute positive effects on craving for alcohol and other drugs of abuse as well as behavioral addiction have been produced by these neuromodulation approaches, but few studies have investigated the effect of brain stimulation on clinical treatment outcomes in addiction.  Stimulation therapies may achieve their effect through direct or indirect neuromodulation of brain regions involved in specific substance use disorders, either acutely or through plastic changes in neuronal transmission, but the shared behavioral underpinnings in all drug use disorders and associated psychopathology are also likely to be involved.

References:

Aksay SS, Hambsch M, Janke C, Bumb JM, Kranaster L, Sartorius A. Alcohol use disorder as a possible predictor of Electroconvulsive Therapy response. The Journal of ECT 2017;33(2):117-121.

Austelle CW, Higgins ES, George MS. Brain stimulation therapies. In: Ebert MH, Martin PR, McVoy M, Ronis RJ, Weissman SH, editors. Current Diagnosis and Treatment: Psychiatry. 4th Edition. New York, NY: McGraw Hill; 2025, pp. 113–25.

Bartholomaeus, Trevisa J, Seymour MC. On the properties of things: John Trevisa’s translation of Bartholomaeus Anglicus De proprietatibus rerum: a critical text. Oxford: Clarendon Press; 1975.

Benabid AL, Chabardes S, Seigneuret E, Pollak P, Fraix V, Krack P, Lebas JF, Grand S, Piallat B. Chapter 34 Functional Neurosurgery: Past, Present, and Future. Neurosurgery 2005;52:265–70.

Bright U, Overstreet C, Levey DF, Gelernter J. Differences and similarities between the genetic architecture of lifetime substance use across different substances. Psychological Medicine 2025;55(e219):1-14.

Broca P. Du siége de la faculté du langage articulé dans l’hémisphère gauche du cerveau. Paris: Victor Masson et Fils; 1865.

Brodmann K. Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth; 1909.

Cohen SL, Bikson M, Badran BW, George MS. A visual and narrative timeline of US FDA milestones for Transcranial Magnetic Stimulation (TMS) devices. Brain Stimulation 2022;15(1):73–5.

Cooper DMF, Rodbell M. ADP is a potent inhibitor of human platelet plasma membrane adenylate cyclase. Nature 1979;282(5738):517–8.

Elson RC, Selverston AI. Mechanisms of gastric rhythm generation in the isolated stomatogastric ganglion of spiny lobsters: bursting pacemaker potentials, synaptic interactions, and muscarinic modulation. Journal of Neurophysiology 1992;68(3):890–907.

Fritsch G, Hitzig E. Ueber die elektrische Erregbarkeit des Grosshirns. Leipzig: Veit; 1870.

George MS, Nahas Z, Molloy M, Speer AM, Oliver NC, Li X-B, Arana GW, Risch SC, Ballenger JC. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biological Psychiatry 2000;48(10):962–70.

Golgi C. Sulla fina anatomia degli organi centrali del sistema nervoso. Reggio-Emilia: Calderini; 1885.

Gorelick DA, Zangen A, George MS. Transcranial magnetic stimulation in the treatment of substance addiction. Annals of the New York Academy of Sciences 2014;1327(1):79–93.

Harel M, Perini I, Kämpe R, Alyagon U, Shalev H, Besser I, Sommer WH, Heilig M, Zangen A. Repetitive transcranial magnetic stimulation in alcohol dependence: a randomized, double-blind, sham-controlled proof-of-concept trial targeting the medial prefrontal and anterior cingulate cortices. Biological Psychiatry 2022;91(12):1061–9.

Hasan ST, Robson WA, Pridie AK, Neal DE. Transcutaneous electrical nerve stimulation and temporary S3 neuromodulation in idiopathic detrusor instability. The Journal of Urology 1996;155(6):2005–11.

Hebb DO. The Organisation of Behavior: A Neuropsychological Theory. New York: Wiley and Sons; 1949.

Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 2006;29(1):565–98.

Illis LS. Central nervous stimulation in neurological disease. J R Soc Med 1983;76(11):905–9.

Kaczmarek LK, Levitan IB. Neuromodulation: the biochemical control of neuronal excitability. New York: Oxford University Press; 1987.

Kalinowsky LB. History of convulsive therapy. Annals of the New York Academy of Sciences 1986;462(1):1–4.

Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 2005;162(8):1403–13.

Kearney-Ramos T, Haney M. Repetitive transcranial magnetic stimulation as a potential treatment approach for cannabis use disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2021;109:110290.

Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology 2010;35(1):217–38.

Kuhn J, Lenartz D, Huff W, Lee S, Koulousakis A, Klosterkoetter J, Sturm V. Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications? J Neurol Neurosurg Psychiatry 2007;78(10):1152-3.

Levy D, Shabat-Simon M, Shalev U, Barnea-Ygael N, Cooper A, Zangen A. Repeated electrical stimulation of reward-related brain regions affects cocaine but not “natural” reinforcement. J Neurosci 2007;27(51):14179.

Lisanby SH. Electroconvulsive therapy for depression. New England Journal of Medicine 2007;357(19):1939–45.

MacLean PD. Some psychiatric implications of physiological studies on frontotemporal portion of limbic system (visceral brain). Electroencephalography and Clinical Neurophysiology 1952;4(4):407–18.

Madeo G, Bonci A. Driving innovation in addiction treatment: role of transcranial magnetic stimulation. Journal of Neural Transmission 2024;131(5):505–8.

Martin PR, Weinberg BA, Bealer BK. Healing Addiction: An Integrated Pharmacopsychosocial Approach to Treatment. Hoboken, New Jersey: John Wiley & Sons, Inc.; 2007.

Martin PR.  Addiction. Historical Vocabulary of Addiction. inhn.org.ebooks. November 24, 2016.

Martin PR.  Conditioning. Historical Vocabulary of Addiction. inhn.org.ebooks. December 26, 2019.

Martin PR.  Kindling. Historical Vocabulary of Addiction. inhn.org.ebooks. July 8, 2021.

Martin PR. Reward. Historical Vocabulary of Addiction, Vol. II. inhn.org.ebooks. April 20, 2023.

Martin PR. Allostasis. Historical Vocabulary of Addiction, Vol. II. inhn.org.ebooks. March 7, 2024.

Maxwell JC, Thompson JJ. A treatise on electricity and magnetism. 3d ed. Oxford: Clarendon; 1904.

Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. British Medical Bulletin 2003;65(1):193–207.

Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45(5):651–60.

Mehta DD, Praecht A, Ward HB, Sanches M, Sorkhou M, Tang VM, Steele VR, Hanlon CA, George TP. A systematic review and meta-analysis of neuromodulation therapies for substance use disorders. Neuropsychopharmacology 2024;49(4):649–80.

Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150(3699):971.

Moss L, Vaidya N. Does comorbid alcohol and substance abuse affect Electroconvulsive Therapy outcome in the treatment of mood disorders? The Journal of ECT 2014;30(1):22-5.

Müller UJ; S V; Voges, J; Heinze, HJ; Galazky, I; Heldmann, M; Scheich, H; Bogerts, B. Successful treatment of chronic resistant alcoholism by Deep Brain Stimulation of nucleus accumbens: first experience with three cases. Pharmacopsychiatry 2009;42(06):288–91.

Murrow RW. Penfield’s prediction: a mechanism for Deep Brain Stimulation. Frontiers in Neurology 2014.

Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science 2007;315(5811):531–4.

Olds J. Self-stimulation of the brain. Its use to study local effects of hunger, sex, and drugs. Science 1958;127(3294):315-24.

Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. Journal of Comparative and Physiological Psychology 1954;47(6):419–27.

Papez JW. A proposed mechanism of emotion. Archives of Neurology & Psychiatry 1937;38(4):725–43.

Penfield W, Erickson TC, Jasper HH, Harrower M. Epilepsy and cerebral localization: a study of the mechanism, treatment and prevention of epileptic seizures. Springfield: C.C. Thomas; 1941.

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proceedings of the National Academy of Sciences 2001;98(2):676–82.

Ramon y Cajal S. Histologie du systeme nerveux de l’homme et des vertebres. 1, Generalites, moelle, ganglions rachidiens, bulbe et protuberance. Paris: Maloine; 1909.

Roper P. Drug addiction, psychotic illness and brain self-stimulation: effective treatment and explanatory hypothesis. Can Med Assoc J 1966;95(21):1080–6.

Salling MC, Martinez D. Brain stimulation in addiction. Neuropsychopharmacology 2016;41(12):2798–809.

Sherrington CS. The Integrative action of the nervous system. New York: C. Scribner’s Sons; 1906.

Soleimani G, Joutsa J, Moussawi K, Siddiqi SH, Kuplicki R, Bikson M, Paulus MP, Fox MD, Hanlon CA, Ekhtiari H. Converging evidence for frontopolar cortex as a target for neuromodulation in addiction treatment. Am J Psychiatry 2024;181:100–14.

Stebbins J. Grants for research of the American Association for the Advancement of Science. Science 1919;50(1303):559–61.

Steele VR, Maxwell AM, Ross TJ, Stein EA, Salmeron BJ. Accelerated intermittent theta-burst stimulation as a treatment for cocaine use disorder: a proof-of-concept study. Frontiers in Neuroscience 2019.

Verdejo-Garcia A, Lorenzetti V, Manning V, Piercy H, Bruno R, Hester R, Pennington D, Tolomeo S, Arunogiri S, Bates ME, Bowden-Jones H, Campanella S, Daughters SB, Kouimtsidis C, Lubman DI, Meyerhoff DJ, Ralph A, Rezapour T, Tavakoli H, Zare-Bidoky M, Zilverstand A, Steele D, Moeller SJ, Paulus M, Baldacchino A, Ekhtiari H. A Roadmap for integrating neuroscience into addiction treatment: a consensus of the Neuroscience Interest Group of the International Society of Addiction Medicine. Frontiers in Psychiatry 2019; Volume 10.

Ward HB, Blyth SH, Kast K. Rewiring recovery: patient-centered neuromodulation interventions for substance use disorders that meet people where they are. Transcranial Magnetic Stimulation 2025;4:100179.

Weiss P. Principles of development: a text in experimental embryology. New York: Henry Holt; 1939.

Wernicke K. Der aphasische Symptomencomplex : eine psychologische Studie auf anatomischer Basis. Breslau: Max Cohn & Weigert; 1874.

Wu H-M, Wang X-L, Chang C-W, Li N, Gao L, Geng N, Ma J-H, Zhao W, Gao G-D. Preliminary findings in ablating the nucleus accumbens using stereotactic surgery for alleviating psychological dependence on alcohol. Neuroscience Letters 2010;473(2):77–81.

Wu Z, He L, Wang Y, Ma Z, Yao Q, Ding X, Wu B. The effect of a single session of transcranial direct current stimulation on inhibitory control and impulsivity in users with excessive internet gaming: a double-blind, randomized controlled trial. Behavioural Brain Research 2025;494:115732.

Zangen A, Moshe H, Martinez D, Barnea-Ygael N, Vapnik T, Bystritsky A, Duffy W, Toder D, Casuto L, Grosz ML, Nunes EV, Ward H, Tendler A, Feifel D, Morales O, Roth Y, Iosifescu DV, Winston J, Wirecki T, Stein A, Deutsch F, Li X, George MS. Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial. World Psychiatry 2021;20(3):397–404.

Zhai T, Salmeron BJ, Gu H, Adinoff B, Stein EA, Yang Y. Functional connectivity of dorsolateral prefrontal cortex predicts cocaine relapse: implications for neuromodulation treatment. Brain Communications 2021;3(2).