Application of functional near-infrared spectroscopy in psychiatry

Ann-Christine Ehlis, Sabrina Schneider, Thomas Dresler, Andreas J. Fallgatter

PII: S1053-8119(13)00320-0DOI: doi: 10.1016/j.neuroimage.2013.03.067Reference: YNIMG 10304

To appear in: NeuroImage

Accepted date: 27 March 2013

Please cite this article as: Ehlis, Ann-Christine, Schneider, Sabrina, Dresler, Thomas,Fallgatter, Andreas J., Application of functional near-infrared spectroscopy in psychiatry,NeuroImage (2013), doi: 10.1016/j.neuroimage.2013.03.067

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Application of functional near-infrared spectroscopy in psychiatry

Ann-Christine Ehlis1,*, Sabrina Schneider1,*, Thomas Dresler1, Andreas J. Fallgatter1

1 Department of Psychiatry and Psychotherapy, University of Tuebingen, Calwerstr. 14,

72076 Tuebingen, Germany

* indicates equal contribution

Corresponding author:

Andreas J. Fallgatter

Department of Psychiatry and Psychotherapy

Psychophysiology and Optical Imaging

University of Tuebingen, Calwerstr. 14, D-72076 Tuebingen, Germany

Phone: +49 7071 29 82300

Fax: +49 7071 29 5379

E-mail: Andreas.Fallgatter@med.uni-tuebingen.de

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Abstract

Two decades ago, the introduction of functional near-infrared spectroscopy (fNIRS) into the

field of neuroscience created new opportunities for investigating neural processes within the

human cerebral cortex. Since then, fNIRS has been increasingly used to conduct functional

activation studies in different neuropsychiatric disorders, most prominently schizophrenic

illnesses, affective disorders and developmental syndromes, such as attention-

deficit/hyperactivity disorder as well as normal and pathological aging. This review article

provides a comprehensive overview of state of the art fNIRS research in psychiatry covering

a wide range of applications, including studies on the phenomenological characterization of

psychiatric disorders, descriptions of life-time developmental aspects, treatment effects, and

genetic influences on neuroimaging data. Finally, methodological shortcomings as well as

current research perspectives and promising future applications of fNIRS in psychiatry are

discussed. We conclude that fNIRS is a valid addition to the range of neuroscientific methods

available to assess neural mechanisms underlying neuropsychiatric disorders. Future

research should particularly focus on expanding the presently used activation paradigms and

cortical regions of interest, while additionally fostering technical and methodological

advances particularly concerning the identification and removal of extracranial influences on

fNIRS data as well as systematic artifact correction. Eventually, fNIRS might be a useful tool

in practical psychiatric settings involving both diagnostics and the complementary treatment

of psychological disorders using, for example, neurofeedback applications.

Keywords

Functional near-infrared spectroscopy (fNIRS), Review, Psychiatry, Mental disorders,

Neuroimaging, Optical Topography

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1. Introduction

Two decades ago, the introduction of functional near-infrared spectroscopy (fNIRS) into the

field of neuroscience created new opportunities for investigating not only healthy, but also

abnormal functional processes within the human cerebral cortex. Starting with basic

validation studies in the early and middle 1990s (e.g., Colier et al., 1995; Duncan et al.,

1996; Hoshi and Tamura, 1993; Kato et al., 1993), fNIRS has been increasingly applied in

psychological studies ever since, particularly focusing on visual (e.g., Herrmann et al.,

2008a; Kato et al., 1993; Obrig et al., 2002), motor (e.g., Gratton et al., 1995; Hirth et al.,

1996; Plichta et al., 2006), language (e.g., Herrmann et al., 2003; Quaresima et al., 2002;

Watanabe et al., 1998), and cognitive paradigms (e.g., Herrmann et al., 2005; Hoshi and

Tamura, 1997; Schroeter et al., 2002) in adult subjects, as well as perceptual and language

tests in infants (e.g., Bartocci et al., 2000; Kotilahti et al., 2005; Kusaka et al., 2004;

Zaramella et al., 2001). Within the last decade, the scope of fNIRS research has been

increasingly extended towards abnormal changes of cerebral hemodynamics during

functional activation studies. To our knowledge, to date, at least 115 original research

articles have employed fNIRS to investigate psychiatric research questions, ranging among

over 900 research articles that applied fNIRS in brain activation studies in general (see

Figure 1). This development clearly emphasizes the increasing relevance of measuring

cerebral hemodynamics in the human brain using fNIRS. Figure 1 illustrates how the number

of publications in the field of human brain research in general, as well as psychiatric

neuroscience in particular, has increased especially within the past ten years.

Beside its versatile applicability, the methodological advancement of fNIRS strongly

contributed to this trend. While early psychiatric neuroscience studies had to rely on

relatively simple single-, two- or four-channel systems (Fallgatter et al., 1997; Hock et al.,

1997; Hock et al., 1996), the extension to multi-channel solutions up to the recent

introduction of a 256-channel system (NIRx Medical Technologies LLC, Glen Head, NY) has

allowed for the investigation of topographic research questions. Moreover, substantial

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progress has been made concerning data analysis (Abdelnour and Huppert, 2009; Akgul et

al., 2005; Cui et al., 2010; Plichta et al., 2007; Schroeter et al., 2004), artifact control and

detection (Izzetoglu et al., 2005; Jang et al., 2009; Sato et al., 2006) and spatial registration

of fNIRS data (Cutini et al., 2011; Singh et al., 2005; Tsuzuki et al., 2012; Tsuzuki et al.,

2007).

Despite some remaining limitations (i.e., restricted depth and spatial resolution; confounding

influence of extracranial signals and anatomical parameters; see discussion), fNIRS exhibits a

number of important advantages making its application attractive for both neuroscience in

general and psychiatric research in particular. First, the combinability of fNIRS with other

brain imaging methods led to a strong increase in studies implementing simultaneous

applications of fNIRS together with Doppler sonography (Hirth et al., 1997; Tachtsidis et al.,

2008), fMRI (Heinzel et al., 2013a; Kennan et al., 2002; Lee et al., 2008; Strangman et al.,

2002), EEG (e.g., Koch et al., 2008; Obrig et al., 2002), PET (Rostrup et al., 2002), and

SPECT (Schytz et al., 2009). Within the combination of different imaging modalities, fNIRS

can thus strongly contribute to a holistic understanding of functional characteristics

underlying neuropsychiatric illnesses. As another important advantage, fNIRS enables

cortical hemodynamic assessments under circumstances where other methods fail (e.g.,

during real-life social interaction or whole body movements). Likewise, its easy applicability

and high ecological validity make fNIRS particularly suitable for psychiatric patients who may

be afraid of tight surroundings (e.g., in MRI/PET scanners) or show motor restlessness (e.g.,

in attention-deficit/hyperactivity disorder [ADHD]) that interferes with motion-sensitive

imaging methods such as MRI, EEG, MEG or PET. Taken together, the benefit of fNIRS in

psychiatric research not only arises from its relative insensitivity to movement artifacts, but is

further linked to its easy applicability and high versatility. Allowing for frequent measurement

repetitions, fNIRS can be easily used for longitudinal studies that become more and more

important for the investigation of the development and treatment of psychiatric disorders.

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This review will provide a comprehensive overview of state of the art fNIRS research in

psychiatry, particularly focusing on applications regarding the phenomenological

characterization, treatment and etiology of psychiatric disorders as well as recent progress

concerning diagnostics and classification (see Figure 2). Published studies available in

databases (pubmed, google scholar) before December 2012 were considered. Finally,

research perspectives and promising future applications of fNIRS in psychiatry will be

addressed.

2.1 Cortical alterations in psychiatric syndromes

A large number of studies aimed at investigating differences between various groups of

psychiatric patients and healthy control samples, in order to describe abnormal brain activity

patterns potentially underlying the etiopathogenesis of a disease. In this respect, previous

studies have mainly focused on schizophrenic (n=20), affective (unipolar and bipolar

depression; n=15) and anxiety disorders (n=9), as well as ADHD (n=4), borderline

personality disorder (n=2), eating disorders (n=2), and addiction (n=1). Additionally, some

analogue studies in healthy subjects were conducted to complement the clinical findings.

Schizophrenia and schizophreniform disorders

The first fNIRS study in schizophrenic patients was published in 1994, focusing on prefrontal

laterality effects and interhemispheric integration during a mirror drawing task and using two

one-channel fNIRS monitors (Okada et al., 1994). In this early work, data were analyzed

mostly on a descriptive level by defining different types of response patterns and analyzing

their relative frequency in controls and patients. As a main result, the authors detected an

aberrant response pattern that was solely observed in schizophrenic patients (dysregulated

pattern) which they interpreted in terms of a disrupted interhemispheric integration. In line

with this finding, another early study confirmed an altered frontal lateralization in

schizophrenic patients during a Go-NoGo task (Fallgatter and Strik, 2000), a result that was

also found in healthy subjects with high schizotypy scores during different cognitive tasks

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(Folley and Park, 2005; Hori et al., 2008a; Hori et al., 2008b). Since then, methodological

advances have allowed for more systematic investigations of cortical function in

schizophrenia using multi-channel fNIRS devices and/or more sophisticated data analysis

strategies. Overall, these studies detected abnormal brain activation patterns in

schizophrenias particularly within the prefrontal cortex (PFC) during various

neurocognitive tasks (e.g., random number generation, Tower of Hanoi, Stroop, verbal

fluency tests, Go/Nogo tasks) (e.g., Kubota et al., 2005; Quaresima et al., 2006, 2009;

Shinba et al., 2004). In practically all cases, reduced hemodynamic responses were observed

in prefrontal areas of schizophrenic patients compared to controls (e.g., Ehlis et al., 2007;

Ikezawa et al., 2009; Quaresima et al., 2009; Shimodera et al., 2012; Shinba et al., 2004;

Takeshi et al., 2010; Zhu et al., 2010) even when samples were matched for performance

differences (Watanabe and Kato, 2004) thus replicating the general finding of cerebral

hypofrontality also found by other neuroimaging methods (for a notable exception in a

patient with resistant catatonic schizophrenia, see Grignon et al. (2008)). Using single-

channel time-resolved spectroscopy (TRS) NIRS, Hoshi et al. (2006) extended the finding of

cerebral hypofrontality to the resting state, for which reduced prefrontal hemoglobin

concentrations were observed particularly in patients with a longer duration of illness (> 10

years). Applying fMRI and fNIRS during the same working memory (WM) task in

schizophrenic patients, Lee et al. (2008) showed a large concordance of fNIRS and fMRI

findings, confirming the general validity of fNIRS data also in clinical samples. By

implementing more fine-grained analyses of the course of the hemodynamic response,

Takizawa et al. found that frontal hemodynamics were slower to respond in schizophrenic

patients during a verbal fluency task (VFT), with a steeper incline (slope) of oxygenated

hemoglobin (O2Hb) concentration at the beginning of the task in healthy subjects (Takizawa

et al., 2008). Additionally, prefrontal hemodynamic data were partly found to be impacted by

clinical characteristics (i.e., age at onset; Koike et al., 2011a), medication effects (Watanabe

and Kato, 2004), and psychopathological symptom scores (Ikezawa et al., 2009; Nishimura

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et al., 2011; Shinba et al., 2004) indicating a connection between PFC function and specific

symptom dimensions. In an interesting attempt to differentiate individuals at different clinical

stages of psychosis using fNIRS during VFT performance, Koike et al. (2011b) demonstrated

that already subjects at ultra-high-risk for developing a psychotic disorder showed reduced

activation within the ventro-lateral PFC as well as fronto-polar and anterior temporal regions

as compared to healthy controls, while not differing significantly from patients in early (first-

episode psychosis) or advanced clinical stages (chronic schizophrenia). In contrast, fNIRS

activation within the dorsolateral prefrontal cortex (DLPFC) was highly sensitive to clinical

progression, with an increasing decline in task-related O2HB concentration across clinical

stages (Koike et al., 2011b). Beyond these studies on different executive functions which

consistently demonstrate the above-reported prefrontal deficits in schizophrenic patients,

Platek et al. (2005) used fNIRS to study the impact of schizotypal personality traits on

prefrontal hemodynamics during different tasks of self-other processing. They reported a

differential association of schizotypy scores and prefrontal activation during self-face

processing (negative correlation) vs. empathy (positive correlation). Similar approaches in

clinical samples of schizophrenic patients are still lacking.

Affective syndromes

Regarding fNIRS research in affective disorders, the first study was again conducted by

Okada et al. (1996) focusing on aspects of frontal lateralization in patients with major

depression (MD) during a mirror drawing task. The main finding was an abnormal laterality

pattern in about half the patients, with higher task-related activation in the non-dominant

compared to the dominant hemisphere, which was never observed in healthy controls.

Following this early work, frontal lobe abnormalities in depression were replicated in a

number of fNIRS studies reporting decreased fronto-temporal oxygenation bilaterally in

patients with unipolar depression using verbal fluency (Herrmann et al., 2004; Matsuo et al.,

2002; Noda et al., 2012; Ohta et al., 2008; Pu et al., 2012a) and WM tasks (Pu et al., 2011;

Schecklmann et al., 2011a). In some of these studies, fronto-temporal activation was found

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to be negatively correlated with symptom severity (Noda et al., 2012) and positively

correlated with adaptive (task-oriented) coping (Pu et al., 2012a). Interestingly, studying

healthy subjects during different affective states, Sato et al. (2011) found negative

correlations between PFC activity and depressed mood during a verbal WM task.

Similarly, in late-onset depression (LOD) task-related activation was found to be reduced in

fronto-temporal areas during different cognitive tasks, and activation deficits particularly

within the fronto-polar cortex were correlated with poor social functioning (Pu et al., 2008;

Pu et al., 2012b). Reduced prefrontal oxygenation in LOD was also shown by Matsuo et al.

(2005), even in the absence of performance differences. Furthermore, patients showed a

reduced vasomotor reactivity in a CO2 inhalation challenge, indicating that a prefrontal

microvascular dysregulation might underlie aspects of frontal lobe dysfunction in LOD.

Besides unipolar and late-onset depression, bipolar disorder has been investigated using

fNIRS. Here, a reduced frontal lobe function could generally be confirmed during WM and

VFT performance (e.g., Schecklmann et al., 2011a), even in remitted/euthymic stages of the

disease (Matsuo et al., 2002; Matsuo et al., 2007; Matsuo et al., 2004). In contrast, Kubota

et al. (2009) found a particularly strong prefrontal oxygenation in bipolar patients in tasks

related to attention and non-verbal cognitive abilities, even in the presence of performance

deficits. In a more complex temporal analysis, Kameyama et al. (2006) were able to

differentiate unipolar from bipolar patients by their fronto-temporal activation patterns: While

patients suffering from unipolar depression mainly showed a blunted O2Hb response in active

task segments of a VFT, bipolar patients exhibited delayed O2Hb responses of normal

amplitude. These findings indicate a potential advantage of the relatively high time-

resolution of fNIRS for the investigation of patients with different affective disorders which

may offer new opportunities in diagnostics.

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Anxiety and related diseases

NIRS studies on anxiety disorders have so far focused on panic disorder, post-traumatic

stress disorder (PTSD) and dental phobia. For panic disorder, fNIRS studies indicate a

reduced activation of particularly the left PFC during cognitive activation in general

(Nishimura et al., 2007; see also Ohta et al., 2008 for findings of bilateral hypofrontality) as

well as during confrontation with anxiety-relevant and other affective material (Akiyoshi et

al., 2003) (for a case report on monozygotic twins discordant for panic disorder, see Tanii et

al. (2010)). In a large sample of 109 panic patients, Nishimura et al. (2009) could

furthermore show a significant correlation between task-related oxygenation changes and

symptom severity, as left prefrontal O2Hb was negatively correlated with the frequency of

panic attacks, whereas right prefrontal HHb was associated with the severity of agoraphobia.

Right prefrontal activation was also enhanced in healthy subjects during anticipatory anxiety

and correlated positively with harm avoidance (Morinaga et al., 2007).

For PTSD, previous findings indicate that following a trauma subtle differences in the

hemodynamic response to trauma-related material might be able to differentiate between

trauma victims with and without a subsequently developed PTSD (Matsuo et al., 2003a):

While both groups showed increased prefrontal O2Hb concentrations during the presentation

of trauma-related material, only PTSD patients additionally exhibited a significant decrease in

HHb along with an enhanced skin conductance response. Moreover, PTSD patients showed

significantly reduced PFC activation during a VFT, and this finding was related to deficits in

attention and concentration (Matsuo et al., 2003b). Together, these studies indicate that

PTSD patients show distinct alterations of cerebral hemodynamics when confronted with

trauma-relevant material, whereas frontal dysfunction during cognitive tasks in general

seems to be a corollary finding due to primary alterations in attentional capacity.

Finally, focusing on hemodynamic responses induced by auditory symptom provocation in

patients with dental phobia, Kchel et al. (2011) reported an increased activation within the

supplementary motor area (SMA) of female patients listening to the sound of a dental drill,

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possibly reflecting the priming of flight behavior during exposure. In a non-clinical sample,

Kudo et al. (2008) found frontal cerebral blood flow to decrease during dentist-related sound

material in subjects who had previously experienced unpleasant dental treatments. Due to

the soundless nature of fNIRS measurements, the method is very well suited to examine

cortical activation provoked by different (phobia-relevant) acoustic stimuli.

Personality disorders

Aiming at one of the most frequently investigated personality disorders, two fNIRS studies

have so far investigated frontal lobe function related to emotion regulation (Ruocco et al.,

2010a) and experiences of social exclusion (Ruocco et al., 2010b) in borderline personality

disorder (BPD). When viewing sad picture material, BPD patients were found to exhibit a

reduced slope of task-related O2Hb increases in left prefrontal channels as compared to

controls (Ruocco et al., 2010a). Moreover, within BPD patients, a reduced O2Hb slope

correlated negatively with clinical symptoms, i.e., ratings of interpersonal difficulties and

abandonment fears, respectively. In contrast, during social exclusion experiences, BPD

patients were found to show increased activation in the (medial) frontal-polar cortex (Ruocco

et al., 2010b), suggesting different neural mechanisms to underlie different symptom

dimensions. Further fNIRS studies on different types of personality disorders are so far

lacking, however, there is some evidence that personality characteristics are related to

frontal lobe hemodynamics as measured with fNIRS in healthy populations. Specifically,

certain personality traits such as novelty seeking (Ito et al., 2005), agreeableness, and

neuroticism (Sato et al., 2012) have been shown to correlate with cortical O2Hb changes. As

personality reflects an important factor in psychiatric practice, future research should strive

to further elucidate the exact relationships.

Eating disorders

To date, fNIRS studies investigating cortical patterns in patients with eating disorders are

sparse. In a first, preliminary fNIRS study on cerebral oxygenation in eating disorders (EDs),

Uehara et al. (2007) examined a mixed group of 11 patients with either anorexia nervosa or

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bulimia nervosa that was compared to a healthy control sample during VFT performance,

and reported differences in task-related oxygenation for both fNIRS parameters (O2Hb,

HHb). In a larger sample of 27 patients, Suda et al. (2010) found significantly reduced

hemodynamic responses in patients with EDs within bilateral fronto-temporal regions.

Moreover, dieting tendency and eating restriction/binge eating scores were correlated with

task-related oxygenation in right fronto-temporal and left orbito-frontal regions, respectively,

indicating a differential involvement of distinct cortical regions in different aspects of ED

symptomatology. So far, fNIRS studies focusing on specific types of EDs are lacking.

Substance abuse

Finally, regarding fNIRS studies in addiction, Schecklmann et al. (2007) studied detoxified

alcohol-dependent patients during a VFT, reporting overall reduced cerebral oxygenation in

fronto-temporal areas despite regular task performance. While Hammers and Suhr (2010)

confirmed a reduced PFC activation in polysubstance-using undergraduates, studies on the

phenomenology of other substance-related or behavioral addictions are so far lacking.

2.2 fNIRS in the assessment of life-time brain function development

About fifteen years ago, researchers started to use fNIRS to elucidate developmental aspects

of cortical functions in psychiatric patients in order to complement pure phenomenological

descriptions of altered brain activity. These studies include examinations at early stages of

psychological anomalies in children, research on normal vs. pathological aging (e.g.,

Alzheimers disease), and studies investigating certain effects of age and aging-related

diseases on specific brain functions.

Attention deficit hyperactivity disorder (ADHD)

Numerically, the majority of fNIRS studies on developmental disorders investigated children

with ADHD. These studies particularly focussed on alterations in PFC activity during different

experimental paradigms involving executive functions, such as Stroop tasks (Jourdan Moser

et al., 2009; Negoro et al., 2010; Xiao et al., 2012), WM tasks (Schecklmann et al., 2010),

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the trail making test (Weber et al., 2005) or Go/NoGo paradigms (Inoue et al., 2012; Xiao et

al., 2012). With the exception of one study, these investigations consistently point towards

an attenuated oxygen metabolism within the frontal lobe, a dysfunction that is of particular

interest in current treatment-oriented research concerning ADHD (see discussion). Recent

fNIRS studies that investigated adult ADHD patients indicate that this hypofrontality seems

to persist throughout development (Ehlis et al., 2008; Schecklmann et al., 2012;

Schecklmann et al., 2008; Schecklmann et al., 2011c).

Autism

Autism Spectrum Disorders (ASD) constitute another developmental pathology that has been

frequently studied using fNIRS within the past few years. Similar to ADHD, most of these

surveys targeted prefrontal hemodynamics (Kawakubo et al., 2009; Kita et al., 2011; Tamura

et al., 2012; Xiao et al., 2012), whereas others investigated effects of auditory stimulation on

temporal areas (Funabiki et al., 2012; Minagawa-Kawai et al., 2009). While Minagawa-Kawai

et al. (2009) demonstrated reduced left-lateralization during phonemic decoding in ASD

patients, Funabiki et al. (2012) did not find abnormal activation patterns in the temporal

cortex during auditory stimulation. However, they discovered reduced prefrontal

hemodynamic responses in ASD children which were interpreted in terms of acoustic

unawareness. Studies on ASD children are complemented by two articles dealing with

pervasive developmental disorder (PDD) in adults, revealing reduced PFC activity during

implicit processing of fearful facial expressions (Nakadoi et al., 2012) as well as verbal

fluency (Kuwabara et al., 2006). Finally, in a mixed sample of ASD children and adults,

Kawakubo et al. (2009) found bilateral PFC hypoactivation in ASD adults during the VFT,

whereas this difference was not apparent in autistic compared to healthy children.

Interestingly, healthy siblings of autistic adults showed a pattern of O2HB concentration

changes that was intermediate between the one found in healthy controls and ASD subjects.

In an innovative attempt to simulate real-life interaction, Suda et al. (2011) used fNIRS to

study fronto-temporal activation in healthy adults during face-to-face conversations and

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found a negative impact of autistic traits on regional cerebral blood volume increases within

the superior temporal sulcus, one of the brain areas putatively involved in the pathology of

ASD. This study demonstrates the potential of fNIRS to examine brain activity patterns even

under relatively naturalistic conditions, which might be of particular relevance when studying

cerebral correlates of social interaction, for example in autistic patients.

NIRS in elderly subjects

Imaging of life-time brain development is not restricted to the examination of developmental

disorders in children and young adults, but is also concerned with depicting

neurophysiological functions in elderly individuals. A study conducted by our own group

emphasizes the importance of age-related effects on cortical hemodynamics during cognitive

tasks: Compared to young adults, elderly subjects showed diminished O2HB concentration

increases and no left-lateralization of brain activation during a VFT (Herrmann et al., 2006).

In a large sample of 325 healthy elderly subjects, we could further show that age predicted

reduced cortical oxygenation within the inferior frontal junction as opposed to increased

activity in the middle frontal and supramarginal gyri (Heinzel et al., 2013b) indicating

compensatory processes or cortical reorganization.

Cerebral oxygenation in patients with Alzheimers Dementia (AD) was frequently investigated

by means of verbal fluency tasks showing impaired hemispheric lateralization (Fallgatter et

al., 1997) as well as reduced O2HB concentration increases (reflecting diminished cortical

activation) within different brain regions, especially the DLPFC (Arai et al., 2006; Herrmann

et al., 2008b) and parietal cortex (Arai et al., 2006; Hock et al., 1997). A lack of left

prefrontal activation during a VFT was also found in elderly subjects suffering from MD

(Matsuo et al., 2000), indicating that respective impairments may exist in different

pathologies during aging. Only few studies have so far described reduced cortical activation

in demented patients for cognitive domains other than verbal fluency, such as visuospatial

orientation (Zeller et al., 2010) or arithmetics (Hock et al., 1996). Innovative attempts to

investigate the effects of aging on cerebral hemodynamics have been made in studies

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comparing different subgroups of pathological developments such as AD patients and

patients with mild cognitive impairment (MCI) (Arai et al., 2006) or by combining fNIRS

with other hemodynamic methods, such as PET (Hock et al., 1997), Doppler Sonography

(van Beek et al., 2012; van Beek et al., 2010) or fMRI (Tak et al., 2011), in order to validate

cortical anomalies observed in dementia. In the latter study, for instance, Tak and colleagues

examined patients with subcortical vascular dementia (SVD) performing a simple hand grip

task using 24-channel fNIRS and simultaneous fMRI in order to elucidate neurovascular

coupling in this particular patient sample. As hypothesized, they found reduced cortical

hemodynamic and metabolic responses in SVD patients within the motor cortex, and a

decreased coupling of cerebral blood flow and the cerebral metabolic rate of oxygen. Beyond

the opportunity of multimodal fNIRS utilization, Tomioka et al. (2009) presented another way

to innovatively implement fNIRS measurements in AD research: Using a 52-channel ETG-

4000 fNIRS system, frontal hemodynamic responses were assessed in AD patients and

healthy controls while performing a) routine driving and b) a collision avoidance task in a

driving simulator. AD was associated with lowered O2HB concentration increases during

collision avoidance but not during low-risk routine driving. Interestingly, prefrontal

oxygenation changes were positively correlated with breaking delays in healthy subjects,

whereas AD patients showed a strong negative correlation, pointing towards a direct link

between behavioural impairments and functional hemodynamic anomalies in AD. Together,

these findings demonstrate the potential of fNIRS in assessing cortical oxygenation in

developmental disorders, with particular advantages of the technique when studying

children, low-health elderly subjects or cortical correlates of real-life functions.

2.3 Using fNIRS to investigate treatment effects

Aiming at the investigation of pharmacological effects, fNIRS has been used to perform

either psychiatric treatment studies or directly examine the effects of pharmacological agents

on neural activation in experimental challenges.

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Pharmacological effects

In the latter context, one study found decreased cortical oxygenation after heroine and

methadone administration compared to saline intake in opioid dependent and healthy

subjects in a resting state setting (Stohler et al., 1999). In contrast, Obata et al. (2003)

reported no effects of acute alcohol intake on O2HB concentration changes in healthy

subjects occipital cortex after visual stimulation. Beyond the investigation of acute

pharmacologic effects, the easy applicability of fNIRS is particularly advantageous in

longitudinal studies that require repeated measurements in a stable experimental setting.

These studies are crucial for the examination of treatment effects following pharmacological,

but also psychotherapeutic and neurophysiological interventions. Richter and colleagues

(2007) were the first to use fNIRS to assess effects of galantamine on word fluency in

patients with dementia over the course of four and eight weeks of treatment. Although brain

activation within the DLPFC differed significantly between healthy elderly and patients, no

treatment effect on brain oxygenation was observed. Furthermore, fNIRS studies have

recently explored neurocognitive effects of methylphenidate (MPH) in ADHD children during

attentional tasks and behavioral control paradigms (Monden et al., 2012; Weber et al.,

2007). Schecklmann et al. (2011b) additionally examined adult ADHD patients and

demonstrated attenuated fronto-temporal hemodynamic responses during olfactory

stimulation in ADHD, whereby activation patterns within the temporal cortex tended to

normalize under MPH medication, an effect potentially mediated by modulations within the

dopaminergic system.

Non-pharmacological treatment

Beyond pharmaceutical treatment opportunities, several studies have focused on treatment

effects of non-pharmacological interventions, such as neurostimulation techniques. In 2000,

Eschweiler and colleagues started utilizing fNIRS to investigate clinical effects of repetitive

transcranial magnetic stimulation (rTMS) applied over the left DLPFC in patients suffering

from MD. In addition to significant symptom improvements after active rTMS, these

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therapeutic effects were predicted by prefrontal hemodynamic responses during a mirror

drawing task (Eschweiler et al., 2000). Moreover, Dresler et al. (2009) reported on an

enhanced recruitment of prefrontal areas in a patient with panic disorder during panic-

related task conditions following an add-on rTMS treatment. Finally, fNIRS has been applied

before and after eye-movement desensitization and reprocessing (EMDR) in patients

suffering from PTSD (Ohtani et al., 2009), animal-assisted psychotherapy for patients with

affective disorders (Aoki et al., 2012), as well as in alcohol-dependent patients during

different phases of withdrawal (Dresler et al., 2012), once again confirming the suitability of

fNIRS for studying treatment effects in longitudinal as well as acute challenge settings.

2.4 Imaging Genetics

Etiologically, psychiatric disorders are strongly influenced by genetic factors with estimated

heritabilities of up to 60% and more (e.g., Faraone and Doyle, 2000), while the influence of

specific common alleles in such non-Mendelian polygenetic disorders is as expected quite low

(e.g., International Schizophrenia Consortium et al., 2009). The imaging genetics approach

aims at connecting the genetic level and the neural network domain with respect to the

pathogenesis of mental disorders. Here, neural activity represents a dimensional

intermediate phenotype (i.e., an endophenotype) that is assumed to be more tightly

connected to the underlying genotype than the overtly diagnosed categorical phenotype (see

Gottesman and Gould, 2003). Although the concept of endophenotypes with its varying

definitions has been under debate throughout the last years and is being discussed in terms

of multivariate genetic models (cf. Kendler and Neale, 2010), it has been proven to be a

valuable tool in unraveling etiological factors of various mental disorders (e.g., Domschke

and Dannlowski, 2010).

With its potential to quickly assess large numbers of participants (easy application, few

contraindications, fast setup), fNIRS is particularly suited to be used in imaging genetics

studies. So far, it has mainly been applied in healthy populations (e.g., Hahn et al., 2011;

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Kopf et al., 2011a; Kopf et al., 2011b; Tupak et al., 2013), while a few studies have also

been conducted in psychiatric (particularly schizophrenic) patients. Takizawa et al. (2009b),

who published one of the first studies in this field, could show that besides reduced

prefrontal oxygenation in patients with schizophrenia, the catechol-O-methyl transferase

(COMT) val158met polymorphism affected neural activation patterns: Within schizophrenic

patients, the val/val homozygous group displayed significantly lower activation than patients

carrying at least one met-allele, an effect that was not found in healthy controls, but could

also be shown for patients with panic disorder (Tanii et al., 2009). As COMT is involved in

prefrontal dopamine degradation, with a much higher catabolization rate in val-allele carriers,

this finding indicates a genetic effect in patients with established alterations in dopaminergic

transmission. According to the authors, these data fit the inverted u-shaped association of

dopamine availability and prefrontal functioning (Tunbridge et al., 2006), with patients and

controls being located on different positions on this function (Takizawa et al., 2009b).

Takizawa et al. (2009a) could furthermore show an effect of the sigma-1 receptor (Sig-1R)

gene, which modulates NMDA and dopamine receptor function, in schizophrenic patients. In

a larger sample, this effect was also observed in controls (Ohi et al., 2011). Reif et al. (2011)

employed two neurocognitive tasks in schizophrenic patients and found that a functional

candidate gene for schizophrenia (i.e., NOS1) encoding nitric oxide (NO) a second

messenger of the NMDA receptor influenced reaction times in the n-back task and

prefrontal activation in the VFT only in patients. Here, the risk variant of the gene that has

been repeatedly linked to schizophrenia (Reif et al., 2006) resulted in prolonged reaction

times and reduced prefrontal activation. In ADHD patients that were administered MPH in a

cross-over design, Oener et al. (2011) found that PFC activation during a Stroop task was

dependent on two polymorphisms within the synaptosomal associated protein 25 (SNAP-25),

indicating interesting interactions between specific SNAP-25 genotypes and MPH-induced

neural effects.

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Taken together, these data show that fNIRS is suited for imaging genetics studies and can

contribute to findings on genetic variants putatively involved in altered dopaminergic and

glutamatergic neurotransmission underlying the pathophysiology of, e.g., schizophrenia.

3. Discussion

In this review, we present the range of fNIRS applications in psychiatric settings that relate

to different major research questions (i.e. phenomenology, life-time development, treatment

effects and genetic influences). Currently, the number of available studies illustrates the

huge potential of the technique in psychiatric contexts, while also allowing us to assess

previous shortcomings and deduce potential future applications and improvements in

experimental designs as well as data analysis strategies.

So far, most fNIRS studies in psychiatric settings have been conducted on prefrontal

activation and the phenomenology of psychological disorders, with the VFT being the most

popular paradigm (Dieler et al., 2012). In the beginning, using only few channels and to

avoid artifacts caused by dark hair, the measurement of prefrontal regions represented a

good starting point for fNIRS research, but given more recent technical developments (e.g.,

multi-channel systems) these approaches should be expanded to include alternative cortical

regions, especially since neuropsychiatric disorders are mostly based on alterations in

distributed cerebral networks. Furthermore, although the VFT as a simple paradigm has been

proven to reliably show differences between patients and controls, it only covers a restricted

aspect of neurocognitive functions (i.e., executive functioning) while being relatively

unspecific, which might partly explain why related cortical activation seems to be altered

relatively independent of the specific diagnosis (see 2.1). In future fNIRS research, activation

paradigms should be chosen that are more specifically tailored to the study population of

interest, thereby increasing the chance of detecting etiologically relevant alterations with

improved diagnostic specificity (see Figure 3 for an example of fNIRS data in schizophrenic

patients vs. controls elicited by the presentation of literal and metaphoric sentences;

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Schneider et al., unpublished data). In light of recent efforts to develop individually tailored

therapeutic strategies for psychiatric illnesses, a more specific assessment of clinically

relevant cortical alterations would constitute an important step along this way.

Against this background, future studies should also focus on the usefulness of fNIRS as a

supportive tool for choosing the most promising treatment approach for a specific patient.

Using fNIRS, neurophysiological markers that might predict treatment outcomes (and may

thus be relevant for personalized medicine) could be easily identified. Whereas studies using

EEG or fMRI have already reported on various biomarkers associated with different

psychiatric diseases that may contribute to therapeutic outcome prediction (e.g., Ehlis et al.,

2012; Wagner et al., 2010), so far only one fNIRS study has investigated the predictive

significance of prefrontal activation patterns for therapeutic efficacy in patients with major

depression (Eschweiler et al., 2000). The authors could show that reduced DLPFC activation

together with a good performance during mental work predicted therapeutic rTMS effects.

Future fNIRS studies could pick up on this finding also with respect to other psychiatric

disorders and the wide range of treatment options.

Besides the investigation of neurophysiological predictors for treatment responsiveness,

fNIRS has recently been started to be implemented as a treatment tool itself, particularly in

terms of neurofeedback interventions. While first results on real-time NIRS-neurofeedback

during motor imagery have already been published (Mihara et al., 2012), our own laboratory

currently assesses the effectiveness of a prefrontal fNIRS feedback training in adult ADHD

patients in a prospective, randomised, controlled treatment study, after first training data in

healthy subjects revealed some promising results (Ehlis et al., in preparation). If positive

therapeutic effects of neurofeedback trainings using fNIRS can be confirmed, such

interventions could offer alternative or additional treatment options in neuropsychiatric

syndromes such as ADHD, anxiety disorders or depression.

Moreover, while fNIRS has been extensively used to phenomenologically describe alterations

in cerebral oxygenation in various groups of psychiatric patients, its potential within the

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diagnostic process has been far less explored. In 2004, Suto et al. (2004) reported that

patients with depression and schizophrenia seemed to show disorder-specific fNIRS patterns

and suggested that fNIRS could provide a useful option for clinical purposes in psychiatry. In

the last few years, more sophisticated approaches (e.g., discriminant analyses; pattern

classification using multiple biomarkers) have been proposed and initial studies for

schizophrenia are available (Azechi et al., 2010; Hahn et al., 2012). Using such approaches,

the correct assignment to the respective classes was about 75%, which indicates that they

might actually offer additional diagnostic information and could aid the diagnostic process,

especially in combination with non-neural markers and prior probability information. Based

on such findings, the Japanese health ministry already confirmed fNIRS as an advanced

medical technology and approved its use "in limited facilities to assist differential diagnosis

of depressive state as a clinical trial for evaluation of its clinical usefulness (the Advanced

Medical Technology Programme)". While we agree that this might be a valuable option in the

future, we feel that more fNIRS research is needed to identify valid markers of

neuropsychiatric illnesses with increased diagnostic specificity, before fNIRS can improve the

diagnostic process in psychiatric disorders.

Despite rapid methodological advances, one of the factors that currently still hamper the use

of fNIRS in practical psychiatric scenarios concerns technical and methodical difficulties that

may complicate the interpretation of fNIRS data in psychological studies, particularly in

clinical populations. Beside its limited depth resolution (e.g., McCormick et al., 1992; Wabnitz

et al., 2010) that prevents an assessment of subcortical areas which ofton play a major role

in neuropsychiatric disorders (e.g., the amygdala in anxiety disorders), the reliability of fNIRS

data has been shown to be affected by anatomical parameters, such as scalp-to-cortex

distance (SCD; Cui et al., 2011; Haeussinger et al., 2011) and peripheral hemodynamic

parameters (i.e., skin perfusion; Kirilina et al., 2012; Takahashi et al., 2011; Tong et al.,

2011). These factors could be potential confounding variables, especially in clinical samples

that might exhibit increased SCD (e.g., in case of cortical atrophy in patients with AD,

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schizophrenia or anorexia nervosa) or enhanced peripheral perfusion due to heightened

emotional or stress responses under certain task conditions (e.g., while processing affective

or trauma-related material in affective disorders or PTSD). Moreover, in light of the ongoing

development of new systems and the recent and current increase in fNIRS applications,

there is a strong need for empirically based, uniform, and user-friendly analysis strategies

that would improve comparability between the wide range of studies and support the

development of clear-cut neuropsychiatric markers. Although commonly accepted

approaches (concerning, e.g., data filtering, motion artifact removal or spatial registration)

exist (e.g., Cui et al., 2010), standardized guidelines for fNIRS data analyses are still lacking.

In summary, we conclude that fNIRS is a valid addition to brain imaging methods assessing

neural mechanisms underlying neuropsychiatric disorders. While the technique has clearly

already shown its potential in the phenomenological description of altered brain activation

patterns in various psychopathological syndromes, future research should particularly focus

on further expanding the presently used activation paradigms and cortical regions of interest.

Moreover, the potential of the technique in practical psychiatric scenarios (e.g., as a

treatment tool [neurofeedback] or an additional aid in diagnostics) should be more

intensively explored. Current attempts to develop systematic tools for artifact correction and

study anatomical and physiological confounds of the fNIRS signal will further pioneer such a

development. In light of the methodological limitations also reported for other imaging

techniques (e.g., several contraindications for fMRI measurements; high sensitivity to

movement artifacts of fMRI/EEG; restrictive measurement environment of fMRI/MEG), fNIRS

clearly represents a valuable alternative, particularly when studying large samples (e.g., in

imaging genetics studies) or severely ill patients (who profit from the quick and

uncomplicated measurement setting) and when experimental settings involve naturalistic

conditions (e.g., during real-life social interaction or whole body movements).

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Figure legends

Figure 1 Graphical time course of published original research articles on fNIRS used

to investigate human cortical functions in general (dark grey line) and in

psychiatric research in particular (light grey line). Annual publications are

depicted.

Figure 2 Overview over current applications of fNIRS in the field of psychiatry.

Numbers in brackets indicate respective page numbers of the present

article, where a certain topic is addressed.

Figure 3 Contrast maps depicting differential increases in O2HB concentration

during a language perception paradigm in healthy control subjects (n=21)

and schizophrenic patients (n=23). Whereas controls show enhanced

oxygenation in both prefrontal and temporo-parietal cortical regions after

viewing metaphoric and literal compared to meaningless German

sentences, no significant oxygenation differences were observed in the

patient group. The figure contains unpublished data from a recently

completed combined EEG/fNIRS study by our own laboratory (Schneider

et al., unpublished data).

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