Jair C. Soares, MD

To solve existential brain challenges spanning neurology, mental health, education, workforce development, and neuroscience—we need a fresh approach to technologies and investing. We need a new investment opportunity: Brain Capital.

Human societies continue to be plagued by

, from mental health disorders and dementia to learning disabilities, the impact of long COVID, and disparities in educational health care access.

Additionally, some of the most persistent social issues—homelessness, crime, death by despair—will be impossible to solve without attention to the root causes and address the treatment and support of individuals with brain disorders and vulnerabilities. If these brain health maladies are not definitively addressed, human communities will have a difficult

 time sustaining themselves both economically and socially

At the same time, deeply comprehending the human brain will make new achievements possible, with brains that thrive from better understanding mental processes such as creativity, innovation, leadership, and entrepreneurship.

We need new ways to move the needle on these unprecedented challenges and opportunities. We need a cross-disciplinary, cross-functional, optimized approach to innovation with a new type of executive, new investment, and new governance.

Figure 1: Brain Capital Technology Overview

Abbreviations: AD, Alzheimer disease; PD, Parkinson disease; MS, multiple sclerosis; ALS, amyotrophic lateral sclerosis; LMICs, low- and middle-income countries; HICs, high-income countries; CVA, cerebrovascular accident; SUD, substance use disorder; TBI, traumatic brain injury.

In the following article, we put forward our case forBrain Capital as a new investment category placing a premium on technological health care innovations that improve brain health and skills. We define Brain Capital Innovation as diverse neuroscience-inspired technologies addressing the confluence of mental health, neurology, education, workforce development, and 

—including resilience, wisdom, and creativity (

 Brain Capital constitutes a promising new opportunity within the impact investment category, also known as environmental, social, and governance (ESG) investing.

Global brain challenges are worsening at a time when our economies and societies are becoming more turbulent. Dependence upon personal technologies is accelerating, with citizens struggling to keep up with unlimited access to massive amounts of information and data, creating increased stress and anxiety. There also have been positive developments, including increasing dependence on knowledge-intensive economic activity, 

 increasing attention to workplace mental health,10 a 

of venture capital activity driving innovation,

 and a higher number of unicorns (companies valued at over USD $1 billion).

 There are new, large-scale public-private partnerships aimed at tackling global mental health (

). Taken together, it can be argued that we are already living in a 

—a neuroscience-inspired, knowledge economy.

Still, there are substantial limitations in our current system of innovation and investing to tackle these brain challenges.

 Approaches to screening, diagnosis, and treatment of mental health disorders are not optimized, compromising our ability to maximize societal brain health and brain skills. Scalable, technological solutions to successfully manage these issues have remained mostly 

—higher education, business, the psychiatry profession, and tech and neurology innovators often do not communicate or collaborate beyond their own disciplines.

While we can applaud emerging evidence-based digital health solutions as scalable, and often more equitable, these technological solutions are mostly at a population level, not personalized enough, and therefore not able to adequately address the diverse and complex nature of individual needs—a precondition to achieve improved outcomes and added value.

personalized and biologically inspired technologies

 struggle to be consistently validated and integrated into clinical workflows and traditional reimbursement models.

 Our understanding of the fundamental neuroscience of these issues needs further advancement, but it is clear that brain disorders have many 

Investment approaches such as the 2/20 general VC model

 can promote undue revenue pressures, create hype cycles that often lead to market failures

 and result in poor governance—especially given that investors cannot always clearly understand or keep pace with the ideas being pursued by technical founders.

 A majority of investments still favor expensive, reimbursed products and services over cost-efficiencies and value-based care. These governance approaches often create 

, which is rife for abuse and mismanagement.

But there are silver linings for addressing these global brain challenges.

Abbreviations: CBT, cognitive behavioral therapy; VR, virtual reality; AR, augmented reality; R&D, research and development; EHR, electronic health record; EMR, electronic medical record.

Frontier neuroscience technologies—spanning omics, digital therapeutics, artificial intelligence, and devices—aim to improve access, screening, prevention, diagnosis, prognosis, and treatment. Concurrently, there is an increasing convergence of these types of solutions as experts, systems, and payors attempt to simplify workflows and minimize fragmentation of new products and services (

A number of boutique and thematic venture funds have arrived to help with brain challenges—the 

 (for mental health); The Ontario Brain Institute’s 

(education)—and there is much activity surrounding social determinants of health (SDoH). While this interdisciplinary work is a vital step forward, we must engineer new approaches and strategic frameworks to move the needle on these unprecedented, collective brain challenges. We need 

 builds prescription digital therapeutics (PDTs) to provide better outcomes for patients, smarter engagement and tracking tools for clinicians, and cost-effective solutions for payers. Pear’s lead product, reSET, for the treatment of substance use disorder, was the first PDT to receive market authorization from the FDA to treat disease. Pear’s second product, reSET-O, for the treatment of opioid use disorder, was the first PDT to receive Breakthrough Designation. Pear’s third product Somryst® for the treatment of chronic insomnia, was the first PDT submitted through the FDA’s traditional 510(k) pathway while simultaneously reviewed through FDA’s Software Precertification Pilot Program.

 is a digital health company aiming to help children reach their full potential by providing engaging training software clinically proven to improve core cognitive performance. Hence, this has value in education and mental health fields. TALi has been developed and validated through a series of pilot studies including randomized controlled trials for acquired brain injury (ABI) and attention in primary school classrooms.

 builds clinically validated cognitive therapeutics, assessments, and diagnostics that look and feel like video games. The company built EndeavorRx, a prescription digital therapeutic video game to help children aged 8 to 12 with attention deficit/hyperactivity disorder (ADHD) and the first game-based therapeutic to get FDA approval. This company has an impact in the mental health, neuroscience, and education realms. Akili has recently entered into a 

 to extend its offerings for early childhood attention impairments.

 game can be employed to improve brain function and teach individuals about logical fallacies and critical thinking in the context of climate change. In the game, players must identify the form of science denialism that matches the possible arguments of a climate denialist, such as “How can models predict climate 100 years out when they can’t get the forecast right next week?” and “Climate models are imperfect so they can’t be trusted.” Overcoming cognitive biases and improving brain function will be key to equipping us to prevent climate change, which conversely will help prevent significant harm to brain health.

 is a health care platform that combines prescription digital therapeutics (PDTx) and care delivery solutions to improve mental and physical health. Happify Health’s first prescription PDTx called Ensemble focuses on treating major depressive disorder (MDD) and generalized anxiety disorder (GAD).

 has developed digital theragnostics, personalized with objective and scalable biomarkers, to prevent, measure, and treat mental illness.They use facial photoplethysmography (PPG) software and deep neural networks to personalize safe and effective gamified "measure-treat-measure" system has been clinically proven to reduce the risk of mental illness in cancer patients, as well as alleviate anxiety in young adults.

 are producing real-world applications to establish music as medicine.They have curated and created therapeutic music using biometrics and AI for people looking to reduce stress and anxiety, increase focus, and unlock their full potential.They are also exploring their capabilities in the dementia space.

 is a flexible virtual platform combined with live, interactive cognitive coaching to enhance how individuals think, interact, and thrive socially. It has 

for anxiety disorders, as well as social and emotional intelligence.

 is a virtual reality digital therapeutic for pain and anxiety. Through patented, targeted techniques, its VR experiences have been shown to 

reduce pain up to 60%, anxiety up to 40%, and need for restraints by 48% in parallel randomized controlled trials

. This company has an impact in mental health, education, and neuroscience.

 is leveraging the power of VR to provide a method of teaching social, behavioral, communication, and life skills for individuals with autism spectrum disorder (ASD) and related diagnoses. FloreoVR has gone through a usability and initial feasibility 

 that supports the technology’s ability to improve fundamental joint attention skills in ASD.

Artificial Intelligence-Based Technologies

 built by researchers at Penn State and Houston Methodist leverages machine learning to aid in the diagnosis of strokes using a smartphone to detect abnormalities in speech and face muscle movements. The app aims to enable caregivers and patients to detect the stroke earlier, enabling better options for the patient. The technology was developed and validated from a 

 having stroke symptoms at Houston Methodist, and it 

 has developed an electroencephalogram headband that detects brain signals and applies machine learning algorithms to provide insights into attention levels, meditation, and sleep. This has applications in neurology and neuroscience.

 is redesigning the mental health therapy experience. It makes evidence-based group therapy available on-demand. Real’s digital platforms allow users access to different therapy pathways, group therapy sessions, journal prompts, and other resources available anytime at their fingertips.

 is developing a platform of brain interface technology that transmits data in and out of the brain via devices implanted inside cerebral blood vessels using minimally invasive endovascular procedures. Synchron’s flagship product, the Stentrode™, is a minimally invasive brain-computer interface that serves as a motor neuroprosthesis for the treatment of paralysis. It is designed to circumvent the dysfunctional neural pathway to convert attempts to move to control digital devices. A first-in-human clinical trial was conducted to evaluate the 

 to improve functional independence for individuals with paralysis.

 develops ultra-high bandwidth brain-machine interfaces to connect humans and computers. Neuralink is currently going through extensive studies with the aim to create the future of brain interfaces by building devices that help individuals with paralysis and inventing new technologies that will expand people’s abilities and the larger community and world.

 is an online learning and education platform that delivers non-fiction, author-driven content by turning bestselling books into bite-sized audio and reading content. By distilling the essence of world literature into 15-minute “Blinks,” the company is adapting to today’s fast-paced society with seamless integration of learning opportunities into everyday life.

 is redesigning higher education by delivering personalized, flexible, and remote-first online degrees in entrepreneurship, sustainability, and technology. Students are mentored by real-world experts and industry leaders, and receive tailored curricula with a focus on creating a more sustainable society.

 is utilizing keystroke behavior to predict episodes of bipolar disorder. The technology tracks smartphone keystrokes and extracts patterns that can impact mood, thereby predicting mood changes and mood risk.

 is moving traditional in-office, paper patient reported outcome scales to the patient’s smartphone with the ability to track mood over time and deliver directly to the patient’s provider.

 has the potential to introduce a paradigm shift to our economic understanding and agency in brain health. By placing a premium on brain health and skills in the economy, Brain Capital technology can be defined as neuroscience-inspired technologies that integrate and optimize for mental health, 

 (including resilience, wisdom, and creativity).

 As an example of complex issues at the confluence of multiple fields, depression is not just a mental disorder—it also constitutes a major risk factor for absenteeism and presenteeism at work, dementia, worsening comorbidities, poor education attainment, cognitive dysfunction, sleep dysregulation, and economic hardship. Severe mental illness drives social injustice syndromes such as homelessness, transgenerational disadvantage, poverty, and crime. Similarly, 

 predisposes to poor educational attainment, reduction in occupational capacity, neurological dysfunction, depression, and dementia, often with transgenerational impacts.

 Later on in neurodegenerative disorders, like Alzheimer disease, Parkinson disease, multiple sclerosis, stroke, and epilepsy, after the onset of the disease, researchers see some similarities, which are probably the result of the neurodegeneration rather than the causes for these disorders. These include problems with speech, gait and unsteadiness, and motor movements in general.

At a societal level, the high prevalence and lasting burden of such issues result in a major strain on economic capacity, leading the World Health Organization, the World Economic Forum, and Harvard Medical School to declare investment in this area an economic “

 Chronic noncommunicable diseases—including cardiovascular disease, diabetes, and obesity—are risk factors for depression, anxiety, cerebrovascular accidents (CVAs), and dementia. Vice versa, mental health disorders such as depression predispose to cardiometabolic disorders. Brain Capital technology has the potential to simultaneously address and mitigate these multisystemic, interdependent, and complex issues. This technology can save the system a fortune in the long run while significantly reducing human suffering—a huge win-win.

Brain Capital technology can also leverage a human-centered approach toward solution development. In other words, Brain Capital technology can utilize a “hybrid” approach that combines the best of technology with the best of human capabilities. For example, many existing Brain Capital technologies have started to combine human coaches with otherwise automated delivery of brain health interventions.

 This approach increases the viability of Brain Capital technologies in numerous ways. It enables a global cohort of advocates for brain health (eg, the coaches and community health workers) to be empowered to deliver brain health advice with both a human touch and advanced technology.

Moreover, responsible innovation and regulation of technology are important guarantors of brain health. While loneliness and lack of purpose remain large sources of poor brain health amplified by the increasingly exploitive uses of technology, Brain Capital technologies that integrate value-driven technology development and a human-centered approach might minimize these issues. Additionally, as many technologies generate large communities of users, the Brain Capital technology approach can be harnessed to accelerate, enrich, and ground these communities in human-centered values. As another example, brain-computer interfaces (BCIs) fuse human capabilities with technology, spanning from health applications (such as managing stroke and movement disorders) to optimizing human performance (such as increasing empathy).

Select examples of promising Convergent Brain Capital startups are outlined in 

, robust operational, governance, and investment innovations will be required to sustain the brain health technology sector.

 We need to bring diverse stakeholders together to form a common language and align on the main value drivers and strategic frameworks as this emerging industry evolves.

There is the opportunity and potential to address the massive underutilization of Brain Capital, especially from older people and meaningfully involve citizens in debate and dialogue about what is needed and possible to support Brain Capital.

To ensure greater replicability of brain research and promote evidence-based approaches translations of the science to benefit humanity, a major push toward standardization for data sharing, curation, and federation is needed. Brain Capital technologies require this foundational infrastructure to be successful. Further, larger validation and real-world studies will be needed to generate critical and dependable foundational data. Philanthropy, health systems, and venture capital must recognize and support this.

On the private investment level, existing ESG approaches have driven positive business and societal value; however, they are incomplete. 

Incorporating Brain Capital into ESG frameworks

—ie, shifting to “B-ESG”—would provide a more comprehensive, robust approach to create long-term positive impacts for the economy, the environment, and all stakeholders.

Brain Capital is an exemplar of the increasing importance of the impact investing space, and a clear sign of the evolution and expansion of ESG. Concurrently, the changing political and social atmosphere has brought more institutional investor interest to ESG: investment firms, foundations, and family offices are increasingly dedicating significant portions of their portfolios to “impact” investments.

Historically, ESG choices have been slim, and scalability was considered nearly impossible. Conversely, addressing the interdisciplinary, multisectoral nature of mental, neurologic, and substance use (MNS) disorders and the fostering of brain performance would make such investing inherently broader and more scalable.

The fact that impact investments and ESG are still in the early stages of becoming mainstream investment areas, means the use of early-stage startups is also the path with the most upside and potentially lucrative returns for investors. As such, investors can take a relatively inexpensive, large position in companies while assuming a more active role in their development and governance. Likewise, accelerators can engage as early movers to provide a boost to the growth and ultimate success of brain tech companies.

Channeling even a small percentage of the existing 

 into Brain Capital innovations and solutions as part of a B-ESG is expected to result in an unprecedented impact.

 A B-ESG approach would also allow us to leverage the financial markets to develop and scale Brain Capital technologies and reduce brain challenges. Finally, a B-ESG approach would send a signal for more investment in venture capital-type vehicles to fund the scaling of neuroscience-backed solutions.

Building on this emerging asset class, it is conceivable that a Brain Capital “exchange traded fund” (ETF) could be developed. ETFs are a type of security that track an index, sector, or commodity and can be purchased or sold on a stock exchange like regular stocks. Such thematic ETFs have already been established for areas such as 

. For a Brain Capital ETF, rules—optimized for brain health and skills building—would need to be generated to determine which company stocks are included and excluded. Potential companies engaged in Brain Capital-building activities may include pharmaceutical and biotech companies, technology companies, health systems and health insurers, educational technology companies, and many others.

The neuroscience innovation market is often riddled with perverse incentives at the detriment of brain health (in social media, for example), as companies and shareholders chase returns. We need a new model to link brain-based innovation with economics—a disciplined approach, methodology, and a set of services for accelerating responsible innovation. To this end, we have developed a “

” model that specifically aims to create and integrate neuroscience advances, policy, diplomacy, economic theories, responsible innovation, and the development and deployment of financial instruments.

We believe that in the 21st century, there are no brains without capital, and no capital without brains. Therefore, a novel approach to building Brain Capital and mitigating global brain challenges is critical to ensuring and improving societal health and for economic growth and prosperity. Brain Capital technology and investment, carefully interwoven into our economy, will advance neuroscience and bring lasting, high-value, durable benefits to our global community. Brain Capital is perhaps the first foray into a new field of “financial engineering in the pursuit of brain building.”

We invite you to consider this Brain Capital framework as you innovate, invest and tackle social challenges.

is co-lead of the OECD-PRODEO Institute Neuroscience-inspired Policy Initiative (NIPI) supported by the Meadows Mental Health Policy Institute. He holds adjunct or advisory roles with IMPACT (Institute for Mental and Physical Health and Clinical Translation) at Deakin University, the Heka Fund (pro bono), Brain Health Nexus at Cohen Veterans Bioscience, the Global Brain Health Institute (GBHI) at the University of California at San Francisco, Baylor College of Medicine, Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez, Chile, University of Texas Health Sciences Center at Houston, and the Davos Alzheimer’s Collaborative

is a managing director of investment management at Boomtown Accelerators.

is a senior financial and business executive. He was CEO of Caliber Home Loans and was prior CEO of CitiMortgage. 

is a leader in energy management and investing, a faculty member at Rice University and the University of Texas, and a cofounder of a mental health policy center and an Emmy Award-winning mental health web channel

is a general partner at IOVC, and faculty at UC Berkeley and Singularity University. She is also appointed by California Governor Gavin Newson to serve as 1 of 13 voting members on California's Mental Health Commission.

is a general partner at Newfund, a cross-Atlantic early-stage firm with investments in health, mental health, edtech, and foodtech. 

is CEO of EBRAINS and director-general of the Human Brain Project of the European Union.

is a professor of neurology, neurosurgery, anesthesiology, and critical care medicine at Johns Hopkins University and the Uniformed Services University of the Health Sciences, and an attending neuro critical care physician at Johns Hopkins Hospital. He serves as co-leader of The BrainHealth Project.

is chief investment officer of Tolleson Wealth Management. He was founding executive director of the Brain Performance Institute at the Center for BrainHealth.

is professor of practice of global mental health in the Department of Global Health and Population at the Harvard T. H. Chan School of Public Health. He was previously director of the Department of Mental Health and Substance Abuse at the World Health Organization.

is a venture capital investor and technology executive. He is founder and co-chair of the Advisory Board of the UCSF Dyslexia Center, and a Californian Mental Health Commissioner.

is Founder of Impact Shares and Principal and Chief Investment Officer with Brookmont Capital Management. 

is an Atlantic Fellow for Equity in Brain Health at GBHI, a Thiel Fellow at Stanford University, and a Steering Committee member for OECD NIPI. 

is CEO of PRODEO and co-founder of the PRODEO Institute. 

is a T. Boone Pickens Distinguished Scientist at the Center for BrainHealth, a co-director at GBHI, professor emeritus at Trinity College Dublin, and founding director of its Institute of Neuroscience.

is director of BrainLat and Senior Atlantic Fellow at the GBHI at University of California, San Francisco (UCSF), San Francisco, California, and Trinity College Dublin, Dublin, Ireland.

is the John S Dunn Sr. Presidential Distinguished Chair, founding chair of Systems Medicine and Bioengineering Department, director of T.T. & W.F. Chao Center for BRAIN and associate director of Houston Methodist Cancer Center, Houston Methodist. He is a professor of radiology, neuroscience, pathology, and laboratory medicine at Weill Cornell Medicine.

is a professor of law and health sciences at University of Surrey; adjunct assistant professor of medicine at the David Geffen School of Medicine at UCLA; partner at Brown, Neri, Smith & Khan, LLP; and a mediator and arbitrator with JAMS, Inc.

is professor, vice chair, and McIngvale Presidential Endowed Chair in the Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine.

is a pediatric physician, CEO, and cofounder of Smileyscope, a VR/AR digital therapeutics company focused on pain and anxiety.

is vice president of medical affairs at Akili Interactive. He also currently serves on the National Advisory Board of the University of Michigan Depression Center. He is an adjunct professor of psychiatry with the New Mexico School of Medicine.

serves as professor and Pat R. Rutherford, Jr. Chair in Psychiatry at McGovern Medical School and as executive director of UTHealth Harris County Psychiatric Center. 

is a physician-scientist, social entrepreneur, and health policy analyst. Besides training in neurology at the Charité University Hospital and Berlin Institute of Health, Germany, he is a postdoctoral researcher at the Massachusetts General Hospital at Harvard Medical School, Boston, USA.

is founder and chief director of the Center for BrainHealth at UT Dallas. She is a distinguished professor at UT Dallas.

is Scientific Leader in Neurology at GE Healthcare. 

 is Founder and Principal Consultant at Great Scott! Consulting. 

is Director of VOICE Global (Valuing Our Intellectual Capital and Experience) and COO of the UK’s National Innovation Centre for Ageing, based at Newcastle University, UK.

isVice President for Integrated Discovery and Information at the Ontarion Brain Institute (OBI).

is Vice President for Business Development and Partnerships at the OBI.

is President and Scientific Director of the OBI. 

is a NHMRC senior principal research fellow, Alfred Deakin professor of psychiatry at Deakin University, and director of the IMPACT Institute at Deakin University.

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A brain capital grand strategy: toward economic reimagination.

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Articles

Brain Capital: a fresh approach to technologies and investing. 

Brain Capital: An Emerging Investment Opportunity

Neuroimaging… is it still a research tool in psychiatry, or is it ready for prime time? In this video, Jair Soares, MD, of the University of Texas at Houston, touches on the main brain imaging techniques and their possible uses in mental health practice.

Video: Neuroimaging. . .  Is It Still a Research Tool in Psychiatry?

Magnetic resonance spectroscopy (MRS) is a useful, noninvasive method of examining alterations in brain neurochemistry that might be associated with the development of bipolar disorder (BD) and the effects of treatment (Soares et al., 1996). It uses the same technology as magnetic resonance imaging and provides a frequency signal intensity spectrum of multiple peaks that reflect the metabolite levels of a localized region in the brain. Magnetic resonance spectroscopy data are usually displayed in the frequency domain, and the area under a specific peak is proportional to the number of protons processing at that frequency (Stanley, 2002). It can assess chemicals containing phosphorus-31 (

C), lithium-7 and fluorine-19. The most commonly used, however, is proton magnetic resonance spectroscopy (

N-acetylaspartate (NAA) is the predominant resonance in the 

H-MRS spectrum of the normal adult human brain. It is an amino acid found in high concentrations in mature neurons and considered to be a marker of neuronal integrity and viability. Reductions in NAA may also reflect impairment in the formation and maintenance of myelin and mitochondrial energy production (Baslow, 2002). In adults with BD, decreased NAA levels were reported in the dorsolateral prefrontal cortex (DLPFC) (Winsberg et al., 2000), orbital frontal gray matter (Cecil et al., 2002) and hippocampus (Bertolino et al., 2003; Deicken et al., 2002). Lower DLPFC NAA levels were also reported in children (Chang et al., 2003) and adolescents (Kusumakar et al., 2002) with BD. Investigating treatment-induced effects, the administration of lithium (Eskalith, Lithobid) during a four-week period was shown to increase brain NAA concentration as indirect evidence of its neurotrophic/neuroprotective effects (Moore et al., 2000; Silverstone et al., 2003). This increase has not been demonstrated with divalproex (Depakote) (Silverstone et al., 2003).

Lithium and divalproex were also recently shown to be protective against dextroamphetamine (a human model of mania)-induced choline decrease (Silverstone et al., 2004). The choline (Cho) peak in the 

H-MRS is considered a potential biomarker for the status of membrane phospholipid metabolism, and basal ganglia Cho/creatine (Cr) is elevated in the euthymic (Kato et al., 1996; Sharma et al., 1992) and depressive state (Hamakawa et al., 1998) in patients with BD. Lithium treatment did not appear to alter Cho resonance in the parietal lobes in seven male patients compared to healthy controls (Stoll et al., 1992) or in the temporal cortex of healthy volunteers (Silverstone et al., 1999). In a case series (n=6), Stoll et al. (1996) demonstrated that oral Cho in combination with lithium was an effective therapy for some patients with treatment-refractory rapid-cycling BD.

Glutamate, glutamine and  γ-aminobutyric acid (GABA) are also of interest, as antiglutamatergic and GABAergic anticonvulsants appear useful in treating BD. In a majority of MRS reports, the Glx region refers to glutamate and glutamine. In a group of adolescents with bipolar depression, a bilateral increase in Glx in the frontal cortex and basal ganglia has been reported (Castillo et al., 2000). Glutamatergic abnormalities may be involved in neurotoxicity that is potentially responsible for specific brain insults in BD. Decreased GABA levels were reported in the occipital cortex in nonmedicated patients with unipolar depression (Sanacora et al., 1999). Occipital cortex GABA concentrations after selective serotonin reuptake inhibitor (Sanacora et al., 2002) and electroconvulsive therapy treatment (Sanacora et al., 2003) were significantly higher than pretreatment concentrations. Patients with BD appear not to have such reduction in GABA levels (Mason et al., 2000).

H-MRS is myo-inositol (mI), which is a substrate for the phosphoinositide cycle. At therapeutic levels, lithium inhibits inositol monophosphatase and polyphosphate-1-phosphatase, which are involved in recycling inositol mono- and polyphosphates to mI (Berridge and Irvine, 1989). Divalproex also decreases the concentration of mI and increases the concentration of inositol monophosphate in rat brains (O'Donnell et al., 2003).

Moore et al. (1999) found decreased mI in the right frontal lobe of depressed patients with BD following acute (five to seven days) lithium administration, which persisted through one month of treatment. However, the patients' clinical state was clearly unchanged at this time, supporting the hypothesis that the initial actions of lithium may occur with a reduction of mI and that this reduction initiates a cascade of secondary changes that are ultimately responsible for lithium's therapeutic efficacy. Consistent with this, Davanzo et al. (2001) observed a significant decrease in anterior cingulate mI/Cr ratios following seven days of lithium therapy in children and adolescents with early-onset BD. Children in a manic phase demonstrated elevated mI/Cr levels within the anterior cingulate cortex.

P-MRS allows in vivo examination of the changes in phosphorus-based membrane metabolism and the effects of medication. In a comprehensive series of studies, one group measured frontal lobe phosphomonoesters (PMEs; precursors of membrane phospholipid metabolism) and demonstrated that frontal lobe PME levels vary with mood state (Deicken et al., 1995a; Kato et al., 1994, 1993). Deicken et al. (1995b) also reported significantly reduced PME in both the right and left temporal lobes in unmedicated euthymic patients compared with healthy controls. An increase in PME concentration with seven and 14 days of lithium administration in the human brain was observed (Yildiz et al., 2001). As patients in the previously mentioned studies were mostly on lithium or off lithium for short periods of time, increased levels of PME could reflect medication effects. This is significant, as lithium inhibits inositol monophosphatase, producing increased levels of PME that would be consistent with increased membrane anabolism.

Bipolar disorder is associated with altered brain chemistry in a number of regions, mainly the DLPFC, basal ganglia, hippocampus and anterior cingulate. The NAA levels in the DLPFC are decreased in patients with BD. It is not clear whether such an abnormality may precede illness onset, or to what extent it may reflect aberrant neurodevelopmental mechanisms, or whether it is related to progressive neuronal loss during the disease process.

Decreased NAA levels may reduce the transfer of acetyl groups required for myelin formation and/or maintenance (Chakraborty et al., 2001). Moreno et al. (2001) demonstrated that NAA synthesis is coupled to energetic (glucose) metabolism using in vivo 

C] glucose infusion. Abnormal brain energy metabolism is also suggested by 

P-MRS findings, such as decreased phosphocreatine (PCr) and intracellular pH (Kato et al., 1994, 1993). A mitochondrial dysfunction hypothesis for the pathophysiology of BD has also been proposed (Konradi et al., 2004).

Studying treatment effects on the neurochemistry of BD is an intriguing area of research (Soares, 2002). The findings of the studies reviewed here show that lithium increases total brain NAA and decreases mI in the anterior cingulate and right frontal lobe, whereas it does not affect the Cho resonance in the parietal lobes. Divalproex also appears to have an effect on the activity of the intracellular phosphoinositol cycle similar to lithium.

Treatment with GABAergic medications increases prefrontal GABA, while treatment with SSRIs is possibly associated with increased occipital cortex GABA concentrations and with a decrease in Cho in the anterior cingulate cortex.

These findings are preliminary and need replication, but they are important. They reflect cellular metabolism and membrane turnover, upon which many essential neuronal functions, such as neurotransmission and second- messenger cascades, are dependent. The application of in vivo MRS technology to the study of the pathophysiology of BD and the mechanisms of action of mood stabilizers is a new field of research. Currently, this is primarily a research tool, but as research evolves and the mechanisms involved are elucidated, it is expected that such tools will be of relevance for diagnosing and monitoring the effects of various treatments.

Our work on this field has been partly supported by MH 01736, the National Alliance for Research on Schizophrenia and Depression, Dana Foundation, the American Foundation for Suicide Prevention, the U.S. Department of Veterans Affairs, the Krus Endowed Chair in Psychiatry (UTHSCSA), and the UTHSCSA GCRC and its imaging core (M01-RR-01346).

Dr. Monkup is a postdoctoral fellow in the division of mood and anxiety disorders in the department of psychiatry at the University of Texas Health Sciences Center at San Antonio.

Dr. Soares is chief of the division of mood and anxiety disorders in the department of psychiatry at the University of Texas Health Sciences Center at San Antonio.

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The number of magnetic resonance spectroscopy studies that assess the levels of different neurochemicals in bipolar disorder has increased considerably in recent years. Abnormalities were reported mainly in the brain regions implicated in the pathophysiology of BD: the dorsolateral prefrontal cortex, cingulated gyrus, hippocampus and basal ganglia. Although these findings are not diagnostic, future research in this area may help to elucidate the pathophysiology of BD and monitor treatment effects.

Jair C. Soares, MD

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