Schizophrenia: Not A Brain Disorder

It is commonly said that schizophrenia is biologically caused. This blog is going to discuss why it is not. It is also said that “schizophrenic” brains are different than normal brains. However, there are three important issues with this idea that are frequently ignored. Many people diagnosed with schizophrenia have no symptoms in common with each other (APA, 2000). This means that researchers could be studying people who have little in common with each other. Second, if we do find that “schizophrenic” brains are different, does that automatically mean that we have found the cause? When we are going through the loss of a loved one, our brains are acting differently than usual. Is this sadness caused by our altered brain functioning or by the loss itself? This logical flaw completely ignores external events, and it seems that many researchers forget that the brain is designed to respond to the environment (Read et al., 2013). The third issue ignored is that one of the external events that can change people’s brain chemistry is antipsychotic medication (Burt, 1977; Chouinard, 1978, 1982, 1991; Ho, 2011; Muller, 1978; Porceddu, 1985).

The term “chemical imbalance” is used by biological psychiatry to explain a vast array of mental health issues, including schizophrenia. This theory was not based on any direct evidence of dopamine over activity. The first drugs that were used to treat schizophrenia in the 1950’s were originally used for sedation before surgery, and it was not understood why they worked for treating schizophrenia (Swazey 1974, Symposium Proceedings 1955). It was only later discovered that these drugs blocked the dopamine receptor, D­2 (Creese 1976). Psychiatry quickly jumped on this and said that if these drugs cure schizophrenia, and these drugs block dopamine receptors, then the cause of schizophrenia must be over stimulation of the dopamine receptors (New York Times, 1979, Read et al., 2013).

However, by that time it had been discovered that the drugs not only caused a block in the dopamine system, but also initiated a response in the brain to compensate for the blockage (Burt, 1977; Chouinard, 1991; Muller, 1978; Porceddu, 1985). “So, over-activity in the dopamine system can be caused by the drugs that are supposedly treating the illness, which is supposed to be caused by over-activity of the dopamine system!”(Read et al., 2013). For this reason, it is essential that studies investigating whether schizophrenia is caused by increased dopamine activity must use participants who have not received antipsychotic drugs. Several reviewers of the evidence at that time confirmed that “no consistent differences between drug-free schizophrenics and normals have been found in terms of dopamine levels” (Bowers 1974; Haracz 1982; Jackson 1986).

After it had been proven that the levels of dopamine in schizophrenics who had never been medicated were normal, another approach was to find differences in the dopamine receptors. However, dopamine receptors have been shown to be increased by antipsychotics (Burt, 1977; Chouinard, 1991; Muller, 1978; Porceddu, 1985), and multiple post-mortem studies show no increases in dopamine receptors in those with schizophrenia who were not treated with antipsychotics (Hietala, 1994; Kornhuber, 1989). The 2009 edition of the popular Comprehensive Textbook of Psychiatry acknowledges that: “Increases in D2 receptors is a consistent finding…but these findings have been largely attributed to a medication effect” (Saddock et al., 2009). Biological psychiatry’s continued failure to prove its lead hypothesis has resulted in investigating other neurotransmitters. As one reviewer noted this search has been no more productive than with dopamine (Dean, 2000). For example, serotonin is another neurotransmitter that is “blocked” by antipsychotic medication, but several studies have found no evidence of serotonin abnormalities in those with schizophrenia (Dean, 2000). The psychiatric textbook The Neuroscience of Clinical Psychiatry, claims that people with schizophrenia have changes in the neurotransmitter GABA, but makes no mention if this research was based on those treated with antipsychotics versus those who were not (Higgins & George, 2013).

Despite the lack of evidence, the chemical imbalance theory remains very popular today (Higgins & George, 2013;; The reason for this is that without it, biological psychiatry could no longer justify its use of antipsychotics, and instead would have to admit that they are simply mind numbing medications that may relieve some symptoms but do not cure anything (New York Times 2008, Ho, 2011) while also having an effect that induces psychosis itself and worsens symptoms in the long term (Chouinard, 1978, 1982, 1991; Muller, 1978; Samaha, 2007). The increase in dopamine receptors makes the brain “supersensitive” to dopamine, which is a neurotransmitter that has been known to mediate psychosis. Thus, if the person ever stops taking their medication, the previously blocked dopamine is now unblocked on a brain that is now very sensitive to dopamine through extra dopamine receptors, potentially leading to psychosis (Chourinard, 1978). Also, long-term use of antipsychotics eventually leads to permanent dopamine dysfunction, which can cause tardive dyskinesia or tardive psychosis. Doctors would then need higher doses of antipsychotics to dampen those symptoms. “The most efficacious treatment is the causative agent itself, the neuroleptic” (Chouinard, 1982). In order for it to be said that antipsychotics are curing a chemical imbalance, it would first have to be proven that there is an imbalance in the first place which I have shown has not been done. Instead, what has been done is proving that antipsychotics themselves cause a chemical imbalance in the brain (Burt, 1977; Chourinard,1978, 1982, 1991; Muller, 1978; Porceddu, 1985; Samaha, 2007).

Another attempt by biological psychiatry is to say that larger ventricles in the brains of schizophrenics is the cause. I already highlighted above some of the issues with this logic, but for many biological psychiatrists this has been taken as incontestable evidence (Higgins & George, 2013). An early review showed that between 6% and 60% of those labeled schizophrenic have enlarged ventricles (Reveley, 1985; Copolov and Crook, 2000). However, we know that this finding is present in other disorders such as alcoholism (Pfefferbaum, 1998) and depression (Kempton, 2011), so this by no means can be used as a cause of schizophrenia. Trauma can also cause cerebral atrophy, ventricular enlargement, and dysfunction of the limbic system (Nemeroff, 2006, Teicher, 2006). Given the fact that a majority of people diagnosed with schizophrenia have been neglected or abused as children, this could easily account for the “evidence” that schizophrenia is a “brain disease” (Connor and Birchwood, 2012; Friedman, 2002; Outcalt and Lysaker, 2012).

Psychiatric medications also cause reduction in brain volume and increases in the ventricles (Dorph-Petersen et al., 2005; Gur, 1998; Ho, 2011; Radua et al., 2012; Weinmann and Aderhold, 2010). This was shown by the discovery that antipsychotics (typical and atypical) cause reduced brain volume in monkeys (Dorph-Petersen et al., 2005). Also, in 2008, it was shown in humans with one of the largest MRI studies to date published in the Archives of General Psychiatry which reported that “The more drugs you’ve been given, the more brain tissue you lose…The prefrontal cortex doesn’t get the input it needs and is being shut down by drugs. That reduces the psychotic symptoms. It also causes the prefrontal cortex to slowly atrophy” (New York Times, 2008, Ho, 2011). This study, which answers some of the most pressing problems in psychiatry, has been largely ignored. In addition to reduced gray matter in the brain, antipsychotic medication has also been linked to reduced white matter in the brain (Ho, 2011; Wang, 2013). Psychiatric textbooks (Higgins & George, 2013) and organizations like the National Institute of Mental Health ( continue to say that schizophrenia is a chronic brain disorder caused by enlarged ventricles, less gray matter, and less white matter in the brain. Of course, without citing any of the above studies showing that these are all caused by other things, especially antipsychotics.

There is not time here to explore some of the other psychological and social explanations for schizophrenia that have demonstrated correlations to higher rates, such as poverty (Wilkinson and Pickett, 2009), gender (Castle, 2000), living in cities (van Os et al., 2009), racism (Karlsen and Nazroo, 2002), and trauma (Shevlin et al., 2007a). Likewise, it can only be briefly noted that two WHO studies have shown that one of the greatest predictors of significantly poorer outcomes for schizophrenia is living in a developed country with continued access to antipsychotic medication (World Health Organization, 1973, 1979). These studies in addition to many others suggest that a one-size-fits-all, medication-based “treatment” of schizophrenia is neither substantiated nor effective, and in many cases makes people much worse (Bockoven, 1975; Bola, 2003; Bola et al., 2011; Carpenter, 1977; Chouinard, 1978, 1982, 1991; Epstein, 1962; Gardos and Cole, 1977; Gardos and Cole, 1978; Gur, 1998; Harding, 1987; Haro, 2011; Harrow, 2007; Hopper, 2000; Lepping et al., 2011; Madsen, 1998; Marshall and Rathborne, 2011; Mathews, 1979; May, 1981; Mosher, 1995; Muller, 1978; Prien, 1971; Rappaport, 1978; Samaha, 2007; Schooler, 1967; Seikkula, 2006; Stip, 2002). From this research, it is at best irresponsible and at worst negligent to be telling people in a fragile, impressionable state they have brain diseases when it is not proven that they do. The implications of this are that our mainstream biological understanding of schizophrenia is unfounded and that standard psychiatric treatment regimens based on unproven causal theories are largely unwarranted.


Works Cited:

APA (2000). Diagnostic and Statistical Manual of Mental Disorders (4th edn, text revision). Washington, DC: American Psychiatric Association.

Bockoven, J. (1975). Comparison of two five-year follow-up studies, American Journal of Psychiatry. 132: 796-801.

Bola, J. (2003). Treatment of acute psychosis without neuroleptics. Journal of Nervous and Mental Disease. 191: 219-29.

Bola, J. et al. (2011). Antipsychotic medication for early episode schizophrenia. Cochrane Database of Systematic Reviews CD006374.

Bowers, M. (1974). Central dopamine turnover in schizophrenic syndromes, Archives of General Psychiatry 31: 50-54.

Burt, D. (1977). Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in the brain. Science 196: 326-27.

Carpenter, W. (1977) The treatment of acute schizophrenia without drugs. American Journal of Psychiatry. 134: 14-20.

Castle, D. (2000). Women and schizophrenia: An epidemiological perspective. In D. Castle et al. (eds), Women and Schizophrenia. Cambridge: Cambridge University Press.

Chouinard, G. (1978). Neuroleptic-induced supersensitivity psychosis, American Journal of Psychiatry 135: 1409-10.

Chouinard, G. (1982). Neuroleptic-induced supersensitivity psychosis, the ‘Hum Course,’ and tardive dyskinesia, Journal of Clinical Psychopharmacology 2: 143-44.

Chouinard, G. (1991). Severe cases of neuroleptic-induced supersensitivity psychosis. Schizophrenia Research 5: 21-33.

Connor, C. and Birchwood, M. (2012). Abuse and dysfunctional affiliations in childhood. Psychosis 4: 19-31

Copolov, D. and Crook, J. (2000). Biological markers and schizophrenia. Australian and New Zealand Journal of Psychiatry 34: S108-12

Creese, I. (1976). Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192: 481-83.

Crow, T. (2010). The continuum of psychosis: 1986-2010. Psychiatric Annals 40:115- 19.

Dean, B. (2000). Signal transmission, rather than reception, is the underlying neurochemical abnormality in schizophrenia. Australian and New Zealand Journal of Psychiatry 34: 560-9.

Deniker, P. (1986). Are the antipsychotic drugs to be withdrawn? In C. Shagass, editor, Biological Psychiatry (New York: Elsevier), 1-9

Dorph-Petersen, K. et al. (2005). The influence of chronic exposure to antipsychotic medications on brain size. Neuropsychopharmacology 30: 1649-61.

Epstein, L. (1962). An approach to the effect of ataraxic drugs on hospital release rates,” American Journal of Psychiatry 119: 246-61.

Friedman, S. et al. (2002). The incidence and influence of early traumatic life events in patients with panic disorder. Anxiety Disorders 16: 259-72

Gardos, G. and Cole, J. (1977). Maintenance antipsychotic therapy: is the cure worse than the disease?. American Journal of Psychiatry. 133: 32-36.

Gardos, G. and Cole, J. (1978). Withdrawal syndromes associated with antipsychotic drugs. American Journal of Psychiatry. 135: 1321-24.

Gur, R. (1998). Subcortical MRI volumes in neuroleptic-naïve and treated patients with schizophrenia. American Journal of Psychiatry 155: 1711-17.

Haracz, J. (1982). The dopamine hypothesis. Schizophrenia Bulletin 8: 438-69.

Harding, C. (1987). The Vermont longitudinal study of persons with severe mental illness, American Journal of Psychiatry 144: 727-34.

Haro, J. (2011). Cross-national clinical and functional remission rates. British Journal of Psychiatry 199: 194-201.

Harrow, M. (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications, Journal of Nervous and Mental Disease 195: 406-14.

Hietala, J. (1994). Striatal D2 dopamine receptor characteristics in neuroleptic naïve schizophrenic patients studied with positron emission tomography. Archives of General Psychiatry 51: 116-23.

Higgins, E., and George, M. (2013). Chapter 23: Schizophrenia. In Neuroscience of Clinical Psychiatry: the pathophysiology of behavior and mental illness (Second ed., pp. 275-286). Philadelphia, PA: Lippincott Williams & Wilkins.

Ho, B. et al. (2011). Long-term antipsychotic treatment and brain volumes. Archives of General Psychiatry 68: 128-37.

Jackson, H. (1986). Is there a schizotoxin? In N. Eisenberg and D. Glasgow (eds), Current Issues in Clinical Psychology. Aldershot: Gower.

Karlsen, S. and Nazroo, J. (2002). Relation between racial discrimination, social class and health among ethnic minority groups. American Journal of Public Health 92: 624-31.

Kempton, M. et al. (2011). Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Archives of General Psychiatry 68: 675-90.

Kornhuber, J. (1989). H-spiperone binding sites in post-mortem brains from schizophrenic patients. Journal of Neural Transmission 75: 1-10.

Lepping, P. et al. (2011). Clinical relevance of findings in trials of antipsychotics: Systematic review. British Journal of Psychiatry 198: 341-5.

Madsen, A. (1998). Neuroleptics in progressive structural brain abnormalities in psychiatric illness. Lancet 352: 784-85.

Marshall, M. and Rathbone, J. (2011). Early intervention for psychosis. Cochrane Database Syst Rev CD004718.

Mathews, S. (1979). A non-neuroleptic treatment for schizophrenia. Schizophrenia Bulletin. 5: 322-32.

May, P. (1981). Schizophrenia: a follow-up study of the results of five forms of treatment. Archives of General Psychiatry. 38: 776-84.

Mosher, L. (1995). The Treatment of Acute Psychosis Without Neuroleptics. International Journal of Social Psychiatry 41: 157-173.

Muller, P. (1978). Dopaminergic supersensitivity after neuroleptics. Psychopharmacology. 60: 1-11.

Nemeroff, C. et al. (2006). Posttraumatic stress disorder. Journal of Psychiatric Research 40: 1-21.

New York Times (1979). Schizophrenia: Vast effort focuses on four areas. New York Times, 13 November, 1979.

New York Times (2008). Using imaging to look at changes in the brain. New York Times, 15 September.

Outcalt, S. and Lysaker, P. (2012). The relationships between trauma history, trait anger, and stigma in persons diagnosed with schizophrenia spectrum disorders. Psychosis 4:32-41.

Pfefferbaum, A. et al. (1998). A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Archives of General Psychiatry 55: 905-12.

Porceddu, M. (1985) [H]SCH 23390 binding sites increase after chronic blockade of d-1 dopamine receptors. European Journal of Pharmacology 118: 367-70.

Prien, R. (1971). Discontinuation of chemotherapy for chronic schizophrenics. Hospital and Community Psychiatry. 22: 20-23.

Radua, J. et al. (2012)., Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neuroscience and Biobehavioral Reviews. Doi:10.1016/j.neuriorev.2012.07.012

Rappaport, M. (1978). Are there schizophrenics for whom drugs may be unnecessary or contraindicated. International Pharmacopsychiatry. 13: 100-11.

Read, J. et al. (2013) Biological Psychiatry’s Lost Cause. In J. Read et al. (eds), Models of Madness (2nd edn). London: Routledge.

Reveley, M. (1985). CT scans in schizophrenia. British Journal of Psychiatry 146: 367-71.

Saddock, B. et al. (2009). Comprehensive Textbook of Psychiatry (9th edn). Philadelphia, PA: Lippincott Williams & Wilkins

Samaha, A. (2007). Breakthrough dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neuroscience 27:2979-86.

Schizophrenia (n.d.). In Mental Health America. Retrieved November 21, 2015, from

Schizophrenia (n.d.). In National Alliance on Mental Illness. Retrieved on November 13, 2015, from

Schooler, N. (1967). One year after discharge. American Journal of Psychiatry 123: 986-95.

Seikkula, J. (2006). Five-Year Experience of First-Episode Nonaffective Psychosis in OpenDialogue Approach. Psychotherapy Research 16 :214-228.

Shevlin, M. et al (2007a). Childhood traumas and hallucinations. Journal of Psychiatric Research 41: 222-8.

Stip, E. (2002). Happy birthday neuroleptics!. European Psychiatry. 17: 115-19.

Swazey, J. (1974) Chlorpromazine in Psychiatry. Cambridge, MA: MIT Press, 78.

Symposium Proceedings, Chlorpromazine and Mental Health (Philadelphia: Lea and Fabiger, 1955), 132.

Teicher, M. et al. (2006). Neurobiological consequences of early stress and childhood maltreatment. Annals of the New York Academy of Sciences 1071: 313-23.

Van Os, J. et al (2009). The clinical epidemiology of schizophrenia. In B. Sadock et al.(eds), Comprehensive Textbook of Psychiatry. Philadelphia, PA: Lipincott, Williams & Wilkins

Wang, Q. et al. (2013). White-matter microstructure in previously drug-naïve patients with schizophrenia after only 6 weeks of treatment. Psychological Medicine 43: 2301-9.

Weinmann, S. and Aderhold, V. (2010). Antipsychotic medication, mortality and neurodegeneration. Psychosis 2: 50-69.

Whitaker, R. (2010). Anatomy Of An Epidemic. New York: Crown Publishers.

Wilkinson, R. and Pickett, K. (2009). The Spirit Level. London: Allen Lane.

World Health Organization (1973), International Pilot Study of Schizophrenia. Geneva: World Health Organization

World Health Organization (1979), Schizophrenia: An International Follow-up Study. New York: Wiley.


Alzheimer’s Disease: In the context of musical memory preservation.

This topic brings back memories, sweet memories for me as it pertains to my beloved paternal grandmother. It opens a new window for me and an understanding about the preservation of musical memory in Alzheimer’s disease. “Mama nnukwu”, as we fondly call her in my local dialect which translates to “big grandma” suffered from Alzheimer’s disease until she passed away at the age of 90 years. Even though, I now have better understanding of her symptoms then especially her memory loss, most intriguing, is why she never really lost her musical memory and the recollection of familiar tunes whenever it played. My big grandma was a member of her church choir until she could no longer attend church services due to her failing health and I recall how at times she will sing endlessly her church hymns and her teenage folklore music but will not remember that she has been fed, who we are or where she is.

Alzheimer’s Disease (AD) affects approximately 5.2 million Americans age 65 and older. By 2030, this number is expected to reach 7.7 million (Alzheimer’s Association, 2011 and Herbert et al., 2003). It is estimated that there may be about 80 million people globally who will be suffering from Alzheimer’s disease by the year 2050.  Episodic memory and instrumental activities of daily living (IADL; e.g., housework, medication adherence, use of transportation, management of money, etc.) are affected early in the course of AD, and are major contributors to the functional disability associated with the disease (Gaugler et al., 2009, Tomaszewski Farias et al.,2009 and McKhann et al.,2011).  The power of music to unlock memories and other cognitive capacities in Alzheimer’s disease is a cherished tenet of clinical neurology, and music is unquestionably a welcome source of comfort to many people with this devastating illness (Clark, warren 2015). In comparison to other memory systems, musical memory is usually considered to be partly independent but in the case of Alzheimer’s disease as well as other dementia, musical memory is surprisingly robust. Musical memory seems not to rely solely on temporal lobe networks, a conclusion supported by evidence that recognition of a musical piece by a patient with bilateral temporal lobe lesion was enhanced by repeated exposure (Samson and Peretz, 2005). Musical memory was found to be preserved in severely amnestic patients with vast lesions of the right medial temporal lobe, the left temporal lobe and parts of left frontal and insular cortex, with similar findings in patients with bilateral temporal lobe damage (Eustache et al., 1990; McChesney-Atkins et al., 2003; Samson and Peretz, 2005; Finke et al., 2012). This strongly suggests that the network encoding musical memory is at least partly independent of other memory systems. Interestingly, it has been shown that different aspects of musical memory can remain intact while brain anatomy and corresponding cognitive functions are massively impaired (Baird and Samson, 2009; Finke et al., 2012).

Musical memory also appears to represent a special case in Alzheimer’s disease, in that it is often surprisingly well preserved (Vanstone and Cuddy, 2010), especially implicit musical memory, which may be spared until very late stages of the disease. Because these findings are mainly derived from case studies, it is not clear under what circumstances which aspect of musical memory is preserved (Baird and Samson, 2009 ; Johnson et al., 2011).  Baird and Samson, 2009  have indeed proposed that this preserved memory for music may be due to intact functioning of brain regions that are relatively spared in Alzheimer’s disease. Furthermore the temporal lobe, and especially temporal pole areas, may be necessary to encode new musical memory, and once musical memories are encoded these areas might not be needed for memory retrieval (Olson et al.,2007; Jonides et al., 2008; Hsieh et al.,2011).  This supports the suggestion of Baird and Samson (2009) that mostly implicit musical memory might be spared in Alzheimer’s disease and thus their study gives a possible explanation for the preservation of long-term musical memory after severe bilateral temporal lobe damage (as in Alzheimer’s disease), since it shows that long-term musical memory representations,  heavily rely on ventral pre-SMA and the caudal anterior cingulate gyrus.

According to the Harvard health letter (2001), it is probably wishful thinking to believe that listening to music is going to immunize anyone against Alzheimer’s disease. But love of music seems to be an innate human quality. Indeed, newborns have musical capabilities and by four months, babies have pronounced preferences for certain musical patterns. We know music can calm us down, rev us up, and break through the most wretched kind of isolation. Mark Jude Tramo, a Harvard medical school neurologist, believes music is a fundamental human need, and maybe especially so for those with neurodegenerative diseases. “Elderly patients with Alzheimer’s disease can’t get together to discuss politics, but they can dance or hum or sing a song that makes them happy,” he says. “We all have to be mindful — whether as family members or health professionals — of the importance of bringing joy into the lives of the sick, allowing them to share in the things that make them happy, whether that involves looking at a book of paintings or listening to swing music.”

So to my late grandma, I say, sing on. I am truly honored to have shared in your care. The experiences I learnt first-hand while helping take care of you at home, has today, so many years later brought me to a greater understanding and appreciation of the day to day struggles and challenges faced by those living with Alzheimer’s disease as well as their  care givers.



Brain health. Music and the mind. (2001)  Harvard Health Letter, 27(2), 4-5. Retrieved from

Baird A & Samson S. (2009). Memory for music in Alzheimer’s disease: unforgettable?.  Neuropsychology Review, 19, 85-101. doi:10.1007/s11065-009-9085-2

Clark C, N & Warren J, D. (2015). Music, memory and mechanisms in Alzheimer’s disease.  Brain, 138, 2122-5. doi:10.1093/brain/awv148

Cuddy L, L & Duffin J. (2005). Music, memory, and Alzheimer’s disease: is music recognition spared in dementia, and how can it be assessed?.  Medical Hypotheses, 64(2), 229-35. Retrieved from

Cuddy L, L, Sikka R & Vanstone A. (2015). Preservation of musical memory and engagement in healthy aging and Alzheimer’s disease.  Annals of the New York Academy of Sciences, 1337, 223-31. doi:10.1111/nyas.12617

El Haj M, Fasotti L & Allain P. (2012). The involuntary nature of music-evoked autobiographical memories in Alzheimer’s disease.  Consciousness & Cognition, 21, 238-46. doi:10.1016/j.concog.2011.12.005

Halpern A, R & O’Connor M, G. (2000). Implicit memory for music in Alzheimer’s disease.  Neuropsychology, 14(3), 391-7. Retrieved from

Hsieh S, Hornberger M, Piguet O & Hodges JR. (2011). Neural basis of music knowledge: evidence from the dementias.  Brain, 134, 2523-34. doi:10.1093/brain/awr190

Hsieh S, Hornberger M, Piguet O & Hodges JR. (2012). Brain correlates of musical and facial emotion recognition: evidence from the dementias.  Neuropsychologia, 50, 1814-22. doi:10.1016/j.neuropsychologia.2012.04.006

Irish M, Cunningham C,J, Walsh JB, Coakley D, Lawlor BA, Robertson IH, et al. (2006). Investigating the enhancing effect of music on autobiographical memory in mild Alzheimer’s disease.  Dementia & Geriatric Cognitive Disorders, 22(1), 108-20. Retrieved from

Jacobsen J,H, Stelzer J, Fritz T,H, Chetelat G, La Joie R & Turner R. (2015). Why musical memory can be preserved in advanced Alzheimer’s disease.  Brain, 138, 2438-50. doi:10.1093/brain/awv135

Menard M, C & Belleville S. (2009). Musical and verbal memory in Alzheimer’s disease: a study of long-term and short-term memory.  Brain & Cognition, 71, 38-45. doi:10.1016/j.bandc.2009.03.008

Quoniam N, Ergis AM, Fossati P, Peretz I, Samson S, Sarazin M, et al. (2003). Implicit and explicit emotional memory for melodies in Alzheimer’s disease and depression.  Annals of the New York Academy of Sciences, 999, 381-4. Retrieved from

Samson S, Dellacherie D & Platel H. (2009). Emotional power of music in patients with memory disorders: clinical implications of cognitive neuroscience.  Annals of the New York Academy of Sciences, 1169, 245-55. doi:10.1111/j.1749-6632.2009.04555.x

Simmons-Stern NR, Deason RG, Brandler B,J, Frustace BS, O’Connor MK, Ally BA, et al. (2012). Music-based memory enhancement in Alzheimer’s disease: promise and limitations.  Neuropsychologia, 50, 3295-303. doi:10.1016/j.neuropsychologia.2012.09.019

Vanstone A, D & Cuddy LL. (2010). Musical memory in Alzheimer disease.  Aging Neuropsychology & Cognition, 17, 108-28. doi:10.1080/13825580903042676


Amyloid-β gone: Clearing a toxic protein from the brain in Alzheimer’s disease

Alzheimer’s disease (AD) afflicts over five million people in the United States. The prevalence of the disease is expected to increase to over 7 million by 2020, and to nearly triple by 2050 (Herbert, Weuve, Scherr & Evans, 2013). Unfortunately, clinically available treatments do not target the underlying pathophysiology of the disease. The mainstay of treatment could be considered palliative at best, and, in the case of antipsychotics, detrimental to extant cognitive functioning. Pinning down the pathophysiology of the disorder will be imperative in order to develop effective treatments. Several recent papers have identified, with more precision, the neurobiological and immunological events that underlie the pathophysiology of the disease. In order to understand these, we must first look at the current scientific understanding of AD.

Interestingly, the only way for a definitive diagnosis of Alzheimer’s disease to be made is via a post-mortem autopsy. Autopsies of individuals with AD show cortical atrophy, plaque formation outside of neurons and tangles inside of neurons (Higgins & George, 2013).

Amyloid plaques are clumps of proteins that adhere to one another. The most concerning protein in these plaques is a 42-amino-acid chain named amyloid-β (Aβ) (Higgins & George, 2013). Aβ is severed from a larger protein that spans the cell membrane named amyloid-β precursor protein (APP) (Pritter et al., 2014). The specific functions of APP have remained elusive, but it is believed to regulate neuronal survival, neural growth and synaptic plasticity (Higgins & George, 2013). Overproduction of Aβ has been identified in familial cases of AD (Citron et al., 1994). Moreover, the toxicity of Aβ has been demonstrated in animal models of AD (Tarasoff-Conway et al., 2015).

In addition to amyloid plaques, neurofibrillary tangles have been identified in the pathology of AD (Tarasoff-Conway et al., 2015). These tangles arise from proteins connected to microtubules within the neuron (Higgins & George, 2013). Microtubules serve as both the internal scaffolding, as well as the transport system, of the neuron (Cooper, 2000). Microtuble-associated proteins (MAPs) anchor the microtubules within the neuron (Cooper, 2000). Tangles begin to form when too many phosphate groups attach to these MAPs, namely tau proteins (Higgins & George, 2013). Without the anchoring provided by the tau proteins, the microtubules and the proteins transported become entangled, and ultimately result in the death of the neuron (Higgins & George, 2013). The cause of the hyperphosphorylation of these tau proteins is uncertain, but research indicates that it may be attributable to the diffusion of soluble Aβ across the cell membrane (Jin et al., 2011).

Recently, there have been several important studies that have further elucidated the pathology of AD. In May of this year, researchers affiliated with the Pahnke Lab in Norway published a paper that could prove integral to our current understanding of AD. In this paper, Krohn et al. (2015) demonstrated that mice deficient in two proteins mimicked symptoms of both early AD, and its precursor – mild cognitive impairment. In addition to impairments in memory and an increase in anxiety, the mice in this study were found to have reduced synaptic density, absent long-term potentiation and astrogliosis – an immune response as a result of neuronal death. These findings are consistent with the pathology seen in post-mortem autopsies of those with AD. The mice were deficient in both neprilysin and the ABC transporter ABCC1. Neprilysin is a major Aβ degrading enzyme and the ABCC1 transporter is important in Aβ clearance from the brain (Krohn et al., 2015). This study is important because it provides a more accurate animal model of the pathology of the early stages of sporadic AD. Sporadic AD accounts for more than 99 percent of the cases of AD and is slower to progress (Krohn et al., 2015). Most of our current understanding of AD is derived from transgenic animal models of the disease in which human genes are spliced into rodent genomes (Krohn et al., 2015). The important point here is that although these transgenic methods have indeed facilitated our current understanding of the disease, they are only reflective of less than one percent of all the cases of AD. Extrapolating these models to sporadic AD would presuppose that, like familial AD, sporadic AD is a disease of the overproduction of Aβ, that early deposition of the protein occurs and that the ratio of soluble to insoluble Aβ is not as significant as it may be (Krohn et al., 2015). In another study, Krohn et al. (2011) demonstrated that the ABCC1 transporter could be activated by thiethylperazine, a drug approved by the FDA to treat nausea and vomiting. This activation resulted in a substantial decrease in Aβ in the brains of these mice.

Another promising avenue of research will certainly involve the recent discovery of lymphatic vessels that connect the brain to the immune system (Louveau et al., 2015). Researchers have known for the last several years that some Aβ is cleared through a so-called “glymphatic system” – a waste removal pathway in the brain that involves glial cells in the CNS (Tarasoff-Conway et al., 2015). Iliff and Nedergaard (2013) found that Aβ removal was decreased by 65 percent in mice bred without the aquaporin-4 channels that are a part of this pathway. Research conducted just prior to the discovery of the CNS lymphatic vessels had identified significantly elevated levels of Aβ in cervical and axillary lymph nodes in transgenic models of AD (Pappolla et al., 2014). The insidious and enigmatic nature of AD has, to date, precluded both early diagnosis and effective treatments that target the underlying pathological process(es). We do know that by the time AD is detected, a sequence of neurobiological events has progressed past the point of intervention to arrest or reverse the disease. Hopefully, further research into how to effectively clear toxic Aβ proteins will drive the development of both treatment options and diagnostic tests.


Citron, M., Vigo-Pelfrey, C., Teplow, D. B., Miller, C., Schenk, D., Johnston, J., Winbald, B., Venizelos, N., Lannfelt, L., & Selkoe, D. J. (1994). Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the swedish familial alzheimer disease mutation. Proceedings of the National Academy of Sciences, 91, 11993-11997.

Cooper G. (2000) The Cell: A Molecular Approach. (2nd ed.). Sunderland, MA: Sinauer Associates. Microtubules. Available from:

Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 Census. Neurology 2013;80(19):1778–83.

Higgins, E., & George, M. (2013). The neuroscience of clinical psychiatry: The pathophysiology of behavior and mental illness (2nd ed.). Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins.

Iliff, J. J., & Nedergaard, M. (2013). Is there a cerebral lymphatic system? Stroke, 44, S93-S95. doi:10.1161/STROKEAHA.112.678698

Jin, M., Shepardson, N., Yang, T., Chen, G., Walsh, D., & Selkoe, D. J. (2011). Soluble amyloid ß-protein dimers isolated from alzheimer cortex directly induce tau hyperphosphorylation and neuritic degeneration. Proceedings of the National Academy of Sciences, 108, 5819-5824. doi:10.1073/pnas.1017033108

Krohn, M., Bracke, A., Avchalumov, Y., Schumacher, T., Hofrichter, J., Paarmann, K., Fröhlich, C., Lange, C., Brüning, T., von Bohlen Und Halbach, O., Pahnke, J. (2015). Accumulation of murine amyloid-beta mimics early alzheimer’s disease. Brain : A Journal of Neurology, 138, 2370-2382. doi:10.1093/brain/awv137 [doi]

Krohn, M., Lange, C., Hofrichter, J., Scheffler, K., Stenzel, J., Steffen, J., Pahnke, J. (2011). Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. The Journal of Clinical Investigation, 121(10), 3924–3931.

Louveau, A., Smirnov, I., Keyes, T., Eccles, D., Rouhani, S., Peske, J., Derecki, N., Castle, D., Mandell, J., Lee, K., Harris, T., Kipnis, J. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature, 16, 523(7560):337-41. DOI: 10.1038/nature14432

Pappolla, M., Sambamurti, K., Vidal, R., Pacheco-Quinto, J., Poeggeler, B., & Matsubara, E. (2014). Evidence for lymphatic Aβ clearance in alzheimer’s transgenic mice. Neurobiology of Disease, 71, 215-219. doi:

Priller, C., Bauer, T., Mitteregger, G., Krebs, B., Kretzschmar, H. A., & Herms, J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. The Journal of Neuroscience, 26, 7212-7221. doi:10.1523/JNEUROSCI.1450-06.2006

Tarasoff-Conway, J., Carare, R., Osorio, R., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B., Frangione, B., Blennow, K., Menard, J., Zetterberg, H., Wisniewski, T., de Leon, M. (2015) Clearance systems in the brain-implications for alzheimer’s disease. Nature Reviews Neurolology. 11:457–470. doi: 10.1038/nrneurol.2015.119.